Substituted inhibitors of menin-mll and methods of use

ABSTRACT

The present disclosure provides methods of inhibiting the interaction of menin with MLL1, MLL2 and MLL-fusion oncoproteins. The methods are useful for the treatment of leukemia, solid cancers, diabetes and other diseases dependent on activity of MLL1, MLL2, MLL fusion proteins, and/or menin. Compositions for use in these methods are also provided.

CROSS-REFERENCE

This application is a divisional of U.S. application Ser. No.16/082,649, filed on Sep. 6, 2018, now U.S. Pat. No. 10,781,218, issuedon Sep. 22, 2020, which is a § 371 U.S. National Phase Entry ofInternational Application No. PCT/US2017/022564, filed on Mar. 15, 2017,which claims the benefit of U.S. Provisional Application No. 62/309,372,filed Mar. 16, 2016; U.S. Provisional Application No. 62/334,369, filedMay 10, 2016; U.S. Provisional Application No. 62/431,389, filed Dec. 7,2016; and U.S. Provisional Application No. 62/446,640, filed Jan. 16,2017, each of which are incorporated herein by reference in theirentireties.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Dec. 17, 2020, isnamed 47535718401SL.txt and is 16 kilobytes in size.

BACKGROUND OF THE INVENTION

The mixed-lineage leukemia (MLL) protein is a histone methyltransferasecritical for the epigenetic regulation of gene transcription. Many acuteleukemias, including acute myeloblastic leukemia (AML), acutelymphoblastic leukemia (ALL) and mixed-lineage leukemia (MLL), arecharacterized by the presence of chimeric MLL fusion proteins thatresult from chromosomal translocations of the MLL gene located atchromosome 11, band q23 (11q23). Chimeric MLL fusion proteins retainapproximately 1,400 amino acids of the N-terminus of MLL, but are fusedwith one of approximately 80 partner proteins (e.g., AF4, AF9, ENL,AF10, ELL, AF6, AF 1p, GAS7). MLL fusion proteins lack the originalhistone methyltransferase activity of the C-terminus of MLL and gain theability to regulate transcription of numerous oncogenes, including HOXand MEIS1, resulting in increased cell proliferation and decreased celldifferentiation, ultimately leading to leukemogenesis.

The menin protein, which is encoded by the Multiple Endocrine Neoplasia(MEN) gene, is a ubiquitously expressed nuclear protein that engages ininteractions with DNA processing and repair proteins, chromatinmodifying proteins and numerous transcription factors (Agarwal, et al.;Horm Metab Res, 2005, 37(6): 369-374). The association of menin with theN-terminus of MLL fusion proteins is necessary for the observedoncogenic activity of MLL fusion proteins. This association has beenshown to constitutively up-regulate the expression of HOX and MEIS1oncogenes and impairs proliferation and differentiation of hematopoieticcells leading to leukemia development. Since menin has been shown tofunction as a general oncogenic cofactor in MLL-related leukemias, theinteraction between menin and MLL fusion proteins and MLL represents apotential chemotherapeutic target.

Patients, especially infants, with leukemias harboring chromosomaltranslocations of the MLL gene have a dismal prognosis, with less than a40% five year survival rate (Slang; Haematologica, 2009, 94(7):984-993). A novel therapeutic strategy is urgently needed to treat theseleukemias. Small molecule inhibitors that block the menin-MLLinteraction are thus valuable targets for treating diseases involvingthe MLL fusion proteins.

SUMMARY OF THE INVENTION

The present disclosure addresses a need in the art by providingcompositions and methods for inhibiting the protein-protein interactionof menin with MLL1, MLL2 and MLL-fusion oncoproteins. The compositionsand methods herein may be useful for treating diseases dependent on theactivity of MLL1, MLL2, MLL fusion proteins, and/or menin such asleukemia, solid cancers, and diabetes. In some embodiments, a compoundof the disclosure interacts non-covalently with menin and inhibits theinteraction of menin with MLL. In some embodiments, a compound of thedisclosure covalently binds menin and inhibits the interaction of meninwith MLL.

In some embodiments of a compound provided herein, the compoundnon-covalently or covalently binds to any one or more isoforms of menin,for example, isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) orisoform 3 (SEQ ID NO: 3) of menin. In certain embodiments, the meninprotein shares 60% or more, 70% or more, 75% or more, 80% or more, 85%or more, 90% or more, 95% or more, or 99% or more sequence identity withisoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2) or isoform 3 (SEQ IDNO: 3).

In one aspect, the present disclosure provides a compound of Formula(I):

or a pharmaceutically acceptable salt, isotopic form, or prodrugthereof, wherein:

H is selected from C₅₋₁₂ carbocycle and 5- to 12-membered heterocycle,each of which is optionally substituted with one or more R⁵⁰;

A is selected from bond, C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle;

B is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

C is 3- to 12-membered heterocycle;

L¹, L² and L³ are each independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂₀—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰, wherein two R⁵⁰ groups attached to thesame atom or different atoms of any one of L¹, L² or L³ can togetheroptionally form a bridge or ring;

R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups or two R^(C)groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

m, n and p are each independently an integer from 0 to 6;

R⁵⁰ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;        and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)²,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   halogen, —NO₂, —CN, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵⁸,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —OC(O)R⁵²,        —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)OR⁵²,        ——NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═S, ═N(R⁵²); and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —NO₂, —CN, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,        —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,        —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═S, and ═N(R⁵²);        and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle,

wherein for a compound or salt of Formula (I), when C is azetidinylene,piperidinylene or piperazinylene and R⁵⁷ is —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,or —NR⁵²S(═O)₂R⁵²:

p is an integer from 1 to 6; and/or

L³ is substituted with one or more R⁵⁰, wherein L³ is not —CH₂CH(OH)—.

In one aspect, the present disclosure provides a compound of Formula(II):

or a pharmaceutically acceptable salt thereof, wherein:

H is selected from C₅₋₁₂ carbocycle and 5- to 12-membered heterocycle,each of which is optionally substituted with one or more R⁵⁰;

A, B and C are each independently selected from C₃₋₁₂ carbocycle and 3-to 12-membered heterocycle;

L¹ and L² are each independently selected from bond, —O—, —S—, —N(R⁵¹)—,—N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰;

L³ is selected from alkylene, alkenylene, and alkynylene, each of whichis substituted with one or more R⁵⁶ and optionally further substitutedwith one or more R⁵⁰;

R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups or two R^(C)_(g)roups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

m, n and p are each independently an integer from 0 to 6;

R⁵⁰ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;        and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁶ is independently selected at each occurrence from:

-   -   —NO₂, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₁₀ alkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle and 3- to 12-membered        heterocycle,    -   wherein each C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl in        R⁵⁶ is independently optionally substituted at each occurrence        with one or more substituents selected from halogen, —NO₂, —CN,        —OR⁵⁹, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁶ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)²,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and    -   further wherein R⁵⁶ optionally forms a bond to ring C; and

R⁵⁹ is independently selected at each occurrence from C₁₋₂₀ alkyl, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle,and 3- to 12-membered heterocycle, each of which is optionallysubstituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH,—OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle,

wherein for a compound or salt of Formula (II), when R⁵⁶ is —CH₃, L³ isnot further substituted with —OH, —NH₂, or —CN.

In some embodiments, for a compound of Formula (II), R^(C) is selectedfrom —C(O)R⁵², —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², ═O, C₁₋₃ alkyl, and C₁₋₃ haloalkyl, or two R^(C) groupsattached to different atoms can together form a C₁₋₃ bridge.

For a compound of Formula (I) or (II), C may be 5- to 12-memberedheterocycle, wherein the heterocycle comprises at least one nitrogenatom. In some embodiments, the heterocycle is saturated. In someembodiments, the heterocycle is selected from piperidinyl andpiperazinyl.

In some embodiments, for a compound of Formula (I), C is selected from

In some embodiments, R⁵⁷ is selected from —S(═O)R⁵², —S(═O)₂R⁵⁸,—S(═O)₂N(R⁵²)², and —NR⁵²S(═O)₂R⁵².

In some embodiments, for a compound of Formula (II), C is selected from

wherein R⁵⁷ is selected from —S(—50 O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²; and C₁₋₁₀ alkyl substituted with one ormore substituents selected from —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, and —NR⁵²S(═O)₂R⁵². In some embodiments, R⁵⁷ is selectedfrom —S(—50 O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵². Insome embodiments, R⁵⁷ is selected from —S(—50 O)CH₃, —S(═O)₂CH₃,—S(═O)₂NH₂, —NHS(═O)₂CH₃, and —S(═O)₂NHCH₃.

For a compound of Formula (I) or (II), R^(C) may be selected from C₁₋₃alkyl and C₁₋₃ haloalkyl.

In some embodiments, for a compound of Formula (I) or (II), H is 5- to12-membered heterocycle, optionally substituted with one or more R⁵⁰; Ais 3- to 12-membered heterocycle; and B is 3- to 12-memberedheterocycle.

For a compound of Formula (I) or (II), H may be 6- to 12-memberedbicyclic heterocycle, optionally substituted with one or more R⁵⁰. Insome embodiments, H is thienopyrimidinyl, optionally substituted withone or more R⁵⁰. In some embodiments, H is

X¹ and X² are each independently selected from CR² and N; X³ and X⁴ areeach independently selected from C and N; Y¹ and Y² are eachindependently selected from CR³, N, NR⁴, 0, and S; R′, R² and R³ areeach independently selected at each occurrence from hydrogen and R⁵⁰;and R⁴ is selected from R⁵¹. In some embodiments, X³ and X⁴ are each C.In some embodiments, X¹ is CR², and R² is selected from hydrogen,halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl. In someembodiments, X¹ is CR², and R² is selected from hydrogen, halogen, —OH,—OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵², —CH₂NH₂,—CH₂N(R⁵²)₂, C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃alkynyl. In some embodiments, X² is N. In some embodiments, Y² is CR³,and R³ is selected from hydrogen, halogen, —OH, —N(R⁵²)₂, —CN,—C(O)OR⁵², C₁₋₃ alkyl, and C₁₋₃ haloalkyl. In some embodiments, R¹ isC₁₋₃ haloalkyl.

For a compound of Formula (I) or (II), A may be 5- to 8-memberedheterocycle, such as 6-membered monocyclic heterocycle. In someembodiments, the heterocycle comprises at least one nitrogen atom. Insome embodiments, A is selected from piperidinylene and piperazinylene,such as

For a compound of Formula (I) or (II), B may be 6- to 12-memberedbicyclic heterocycle. In some embodiments, the heterocycle comprises atleast one nitrogen atom. In some embodiments, B is indolylene, such as

optionally substituted with one or more R^(B).

In some embodiments, for a compound of Formula (I) or (II), H isthienopyrimidinyl substituted with one or more R⁵⁰; A is selected frompiperidinylene and piperazinylene; and B is indolylene.

For a compound of Formula (I) or (II), H may be substituted with—CH₂CF₃. In some embodiments, m is 0. In some embodiments, n is aninteger from 1 to 3. In some embodiments, L¹ comprises less than 10atoms. In some embodiments, L¹ is —N(R⁵¹)—. In some embodiments, L²comprises less than 10 atoms. In some embodiments, L² is C₁₋₄ alkylene,optionally substituted with one or more R⁵⁰. In some embodiments, L² isselected from —CH₂—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —N(R⁵¹)C(O)—, and—N(R⁵¹)S(O)₂—. In some embodiments, L³ comprises less than 20 atoms. Insome embodiments, L³ is C₁₋₆ alkylene, optionally substituted with oneor more R⁵⁰. In some embodiments, L³ is C₂ alkylene substituted with atleast one C₁₋₃ alkyl or C₁₋₃ haloalkyl, and optionally furthersubstituted with one or more R⁵⁰. In some embodiments, L³ is substitutedwith ═O, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₃ alkyl(cyclopropyl), C₁₋₃alkyl(NR⁵²C(O)R⁵²) or —O(C₁₋₆ alkyl). In some embodiments, L³ issubstituted with —CH₃. In some embodiments, a compound of Formula (I) or(II) is selected from Table 1.

For a compound of Formula (I), L³ may be selected from

Optionally, R⁵⁰ is methyl. In some embodiments, for a compound ofFormula (II), L³ is selected from

Optionally, R⁵⁶ is methyl. In certain aspects, the present disclosureprovides a substantially pure stereoisomer of a compound of Formula (I)or (II). Optionally, the stereoisomer is provided in at least 90%enantiomeric excess.

In some embodiments, for a compound of Formula (I) or (II), H isthienopyrimidinyl, optionally substituted with one or more R⁵⁰; A is 3-to 12-membered heterocycle; B is 6- to 12-membered bicyclic heterocycle;m is an integer from 0 to 3; and n is an integer from 1 to 3.

In some embodiments, for a compound of Formula (I):

H is thienopyrimidinyl, optionally substituted with one or more R⁵⁰;

A is selected from piperidinylene and piperazinylene;

B is indolylene;

L¹ and L² are each independently selected from —O—, —S—, —NH—, and—CH₂—;

L³ is selected from bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—,—C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—, —C(O)N(R⁵¹)C(O)—,—C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—,—OC(O)N(R⁵¹)—, —C(NR⁵¹)—, —N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—,—N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—, —OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—,—S(O)₂O—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—,—N(R⁵¹)S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene,alkynylene, heteroalkylene, heroalkenylene, and heteroalkynylene, eachof which is optionally substituted with one or more R⁵⁰, wherein two R⁵⁰groups attached to the same atom or different atoms of L³ can togetheroptionally form a ring;

R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups or two R^(C)groups attached to the same atom or different atoms can togetheroptionally form a ring;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 6;

R⁵⁷ is selected from:

-   -   —S(—50 O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —S(—50 O)R⁵², —S(═O)₂R⁵⁸,        —S(═O)₂N(R⁵²)², —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, and -P(O)(R⁵²)₂; and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle.

In some embodiments, for a compound of Formula (II):

H is thienopyrimidinyl, optionally substituted with one or more R⁵⁰;

A is selected from piperidinylene and piperazinylene;

B is indolylene;

L¹ and L² are each independently selected from —O—, —S—, —NH—, and—CH₂—;

L³ is selected from C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene,each of which is substituted with one or more R⁵⁶ and optionally furthersubstituted with one or more R⁵⁰;

R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups or two R^(C)groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 6;

R⁵⁶ is independently selected at each occurrence from:

-   -   —OR⁵⁹, —O—, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl,    -   wherein each C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl in        R⁵⁶ is independently optionally substituted at each occurrence        with one or more substituents selected from halogen, —NO₂, —CN,        —OR⁵⁹, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁶ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)²,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and    -   further wherein R⁵⁶ optionally forms a bond to ring C; and

R⁵⁹ is independently selected at each occurrence from C₁₋₂₀ alkyl, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle,and 3- to 12-membered heterocycle, each of which is optionallysubstituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH,—OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle.

For a compound of Formula (I), R⁵⁷ may be selected from —S(—50 O)₂R⁵⁸,—S(═O)₂N(R⁵²)₂, and —S(═O)₂NR⁵³R⁵⁴, such as —S(—50 O)₂CH₃ and —S(—50O)₂NHCH₃. For a compound of Formula (II), C may be substituted with—S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, or —S(—50 O)₂NR⁵³R⁵⁴.

In some embodiments, for a compound of Formula (I) or (II), H is

and R² is selected from hydrogen, halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂,—CN, C₁₋₃ alkyl, C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, andC₂₋₃ alkynyl. Optionally, R² is selected from —NH₂, —CH₃, and —NHCH₃. Insome embodiments, for a compound of Formula (I) or (II), H is

and R² is selected from hydrogen, halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂,—CN, C₁₋₃ alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl,C₂₋₃ alkenyl, and C₂₋₃ alkynyl. Optionally, R² is selected from —NH₂,—CH₃, —OCH₃, —CH₂OH, and —NHCH₃. For a compound of Formula (I) or (II),L³ may be selected from

In certain aspects, the present disclosure provides a pharmaceuticalcomposition comprising a compound or salt of Formula (I) or (II) and apharmaceutically acceptable carrier. In some embodiments, thepharmaceutical composition is formulated for oral administration. Insome embodiments, the pharmaceutical composition is formulated forinjection.

In certain aspects, the present disclosure provides a method ofinhibiting an interaction of menin with one or more of MLL1, MLL2, anMLL fusion protein, and an MLL Partial Tandem Duplication, comprisingcontacting menin with an effective amount of a compound or salt ofFormula (I) or (II). In certain aspects, the present disclosure providesa method of inhibiting a menin-MLL interaction, comprising contactingmenin with an effective amount of a compound or salt of Formula (I) or(II), wherein inhibition of the interaction is evidenced by a reductionin expression of an MLL fusion protein target gene. In certain aspects,the present disclosure provides a method of stabilizing menin,comprising contacting menin with a compound or salt of Formula (I) or(II).

In practicing any of the subject methods, the MLL fusion protein targetgene may be HOXA9, DLX2, or MEIS1. The contacting may comprisecontacting a cell that expresses menin. In some embodiments, the methodcomprises administering a second therapeutic agent. In some embodiments,the contacting takes place in vivo. In some embodiments, the contactingtakes place in vitro.

In certain aspects, the present disclosure provides a method of treatinga disease or condition associated with MLL fusion proteins, comprisingadministering to a subject in need thereof an effective amount of acompound or salt of Formula (I) or (II). In certain aspects, the presentdisclosure provides a method of treating a disease or condition in asubject, comprising administering to the subject a therapeuticallyeffective amount of a pharmaceutical composition of a compound or saltof Formula (I) or (II). In some embodiments, the disease or conditioncomprises a leukemia, hematologic malignancy, solid tumor cancer,prostate cancer, breast cancer, liver cancer, brain tumor, or diabetes.In some embodiments, the leukemia comprises AML, ALL, Mixed LineageLeukemia or a leukemia with Partial Tandem Duplications of MLL.

In certain aspects, the present disclosure provides a method of treatinga disorder mediated by chromosomal rearrangement on chromosome 11q23 ina subject in need thereof, the method comprising administering to thesubject a therapeutically effective amount of a compound or salt ofFormula (I) or (II). In certain aspects, the present disclosure providesa method of treating a disorder mediated by an interaction between meninand another protein, comprising administering to a subject in needthereof a therapeutically effective amount of a compound or salt ofFormula (I) or (II). In some embodiments, the subject is a human.

In certain aspects, the present disclosure provides a kit comprising apharmaceutical composition described herein and instructions for usingthe composition to treat a subject suffering from a disease or conditionmediated by an interaction between menin and another protein.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1 is an amino acid sequence of human menin, isoform 1 (SEQ ID NO:1).

FIG. 2 is an amino acid sequence of human menin, isoform 2 (SEQ ID NO:2).

FIG. 3 is an amino acid sequence of human menin, isoform 3 (SEQ ID NO:3).

FIG. 4 depicts the change in volume of MV4;11 tumors in vehicle andcompound treated mice.

FIG. 5 depicts the luminescence of MV4;11-luc tumors in vehicle andcompound treated xenotransplantation mouse models of MLL leukemia after6 days of treatment.

FIG. 6 depicts gene expression changes of DLX2, HOXA9, MEIS1 and CD11Bin bone marrow samples taken from the vehicle and compound treated miceshown in FIG. 5.

FIG. 7 depicts the survival curve of vehicle and compound treated micewith MV4;11-luc tumors.

FIG. 8 depicts the change in volume of MV4;11 tumors in vehicle andcompound treated mice.

FIG. 9 depicts gene expression changes of HOXA9, MEIS1 and CD11B in bonemarrow samples taken from vehicle and compound treated mice.

FIG. 10 depicts the survival curve of vehicle and compound treated micewith MOLM13 tumors.

FIG. 11 depicts the luminescence of MV4;11-luc tumors in vehicle andcompound treated xenotransplantation mouse models of MLL leukemia after6 days of treatment.

FIG. 12 depicts gene expression changes of HOXA9,114EISI and CD11B inbone marrow samples taken from the vehicle and compound treated miceshown in FIG. 11.

FIG. 13 depicts the surivival curve of vehicle and compound treated micewith MOLM13 tumors.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in theart to which this invention belongs.

“MLL fusion protein” refers to a protein with an N-terminal fragment ofMLL fused with a partner protein. Non-limiting examples of a partnerprotein include 11q23, 11q23.3, 11q24, 1p13.1, 1p32 (EPS15), 21q22,9p13.3, 9p22 (MLLT3/AF9), ABI1, ABI2, ACACA, ACTN4, AFF1/AF4, AFF3/LAF4,AFF4/AFS, AKAP13, AP2A2, ARHGEF12, ARHGEF17, BCL9L, BTBD18, BUD13,C2CD3, CASCS, CASP8AP2, CBL, CEP164, CEP170B, CREBBP, DCP1A, DCPS,EEFSEC/SELB, ELL, EPS15, FLNA, FNBP1, FOXO3, GAS7, GMPS, KIAA1524,LAMC3, LOC100131626, MAML2, ME2, MLLT1/ENL, MLLT10/AF10, MLLT11/AF1Q,MLLT3/AF9, MLLT4/AF6, MLLT6/AF17, MYH11, MYO1F, NA, NEBL, NRIP3, PDS5A,PICALM, PRPF19, PTD, RUNDC3B, SEPT11, SEPT2, SEPT5, SEPT6, SEPT9, SMAP1,TET1, TNRC18, TOP3A, VAV1, and Xq26.3 (CT45A2). MLL fusion proteins maybe created through the joining of a gene that codes for an MLL proteinand a gene that codes for a partner protein creating a fusion gene.Translation of this fusion gene may result in a single or multiplepolypeptides with functional properties derived from each of theoriginal proteins.

The term “C_(x-y)” or “C_(x)-C_(y)” when used in conjunction with achemical moiety, such as alkyl, alkenyl, or alkynyl is meant to includegroups that contain from x to y carbons in the chain. For example, theterm “C_(x-y) alkyl” refers to substituted or unsubstituted saturatedhydrocarbon groups, including straight-chain alkyl and branched-chainalkyl groups that contain from x to y carbons in the chain The terms“C_(x-y) alkenyl” and “C_(x-y) alkynyl” refer to substituted orunsubstituted straight-chain or branched-chain unsaturated hydrocarbongroups that contain at least one double or triple bond respectively.Unless stated otherwise specifically in the specification, a C_(x),alkyl, C_(x), alkenyl, or C_(x), alkynyl is optionally substituted byone or more substituents such as those substituents described herein.

“Carbocycle” refers to a saturated, unsaturated or aromatic ring inwhich each atom of the ring is a carbon atom. Carbocycle may include 3-to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle maybe selected from saturated, unsaturated, and aromatic rings. In someembodiments, the carbocycle is an aryl. In some embodiments, thecarbocycle is a cycloalkyl. In some embodiments, the carbocycle is acycloalkenyl. In an exemplary embodiment, an aromatic ring, e.g.,phenyl, may be fused to a saturated or unsaturated ring, e.g.,cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated,unsaturated and aromatic bicyclic rings, as valence permits, areincluded in the definition of carbocyclic. Exemplary carbocycles includecyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, andnaphthyl. Unless stated otherwise specifically in the specification, acarbocycle is optionally substituted by one or more substituents such asthose substituents described herein.

“Heterocycle” refers to a saturated, unsaturated or aromatic ringcomprising one or more heteroatoms. Exemplary heteroatoms include N, O,Si, P, B, and S atoms. Heterocycles include 3- to 10-membered monocyclicrings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridgedrings. Each ring of a bicyclic heterocycle may be selected fromsaturated, unsaturated, and aromatic rings. The heterocycle may beattached to the rest of the molecule through any atom of theheterocycle, valence permitting, such as a carbon or nitrogen atom ofthe heterocycle. In some embodiments, the heterocycle is a heteroaryl.In some embodiments, the heterocycle is a heterocycloalkyl. In anexemplary embodiment, a heterocycle, e.g., pyridyl, may be fused to asaturated or unsaturated ring, e.g., cyclohexane, cyclopentane, orcyclohexene.

“Heteroaryl” refers to a 3- to 12-membered aromatic ring that comprisesat least one heteroatom wherein each heteroatom may be independentlyselected from N, O, and S. As used herein, the heteroaryl ring may beselected from monocyclic or bicyclic and fused or bridged ring systemsrings wherein at least one of the rings in the ring system is aromatic,i.e., it contains a cyclic, delocalized (4n+2) π-electron system inaccordance with the Hiickel theory. The heteroatom(s) in the heteroarylmay be optionally oxidized. One or more nitrogen atoms, if present, areoptionally quaternized. The heteroaryl may be attached to the rest ofthe molecule through any atom of the heteroaryl, valence permitting,such as a carbon or nitrogen atom of the heteroaryl. Examples ofheteroaryls include, but are not limited to, azepinyl, acridinyl,benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl,benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl,benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl,benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl,benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl,benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl,cyclopenta[d]pyrimidinyl,6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl,5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl,6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl,dibenzothiophenyl, furanyl, furanonyl, furo[3,2-c]pyridinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridazinyl,5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl,indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl,isoquinolyl, indolizinyl, isoxazolyl,5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl,1,6-naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl,5,6,6a,7,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl,phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl,pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,5,6,7,8-tetrahydroquinazolinyl,5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl,6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl,5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl,triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl,thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pridinyl, and thiophenyl (i.e.thienyl). Unless stated otherwise specifically in the specification, theterm “heteroaryl” is meant to include heteroaryls as defined above whichare optionally substituted by one or more substituents such as thosesubstituents described herein.

Compounds of the present disclosure also include crystalline andamorphous forms of those compounds, pharmaceutically acceptable salts,and active metabolites of these compounds having the same type ofactivity, including, for example, polymorphs, pseudopolymorphs,solvates, hydrates, unsolvated polymorphs (including anhydrates),conformational polymorphs, and amorphous forms of the compounds, as wellas mixtures thereof

The compounds described herein may exhibit their natural isotopicabundance, or one or more of the atoms may be artificially enriched in aparticular isotope having the same atomic number, but an atomic mass ormass number different from the atomic mass or mass number predominantlyfound in nature. All isotopic variations of the compounds of the presentdisclosure, whether radioactive or not, are encompassed within the scopeof the present disclosure. For example, hydrogen has three naturallyoccurring isotopes, denoted 41 (protium), ²H (deuterium), and ³H(tritium). Protium is the most abundant isotope of hydrogen in nature.Enriching for deuterium may afford certain therapeutic advantages, suchas increased in vivo half-life and/or exposure, or may provide acompound useful for investigating in vivo routes of drug elimination andmetabolism. Isotopically-enriched compounds may be prepared byconventional techniques well known to those skilled in the art.

“Isomers” are different compounds that have the same molecular formula.“Stereoisomers” are isomers that differ only in the way the atoms arearranged in space. “Enantiomers” are a pair of stereoisomers that arenon superimposable mirror images of each other. A 1:1 mixture of a pairof enantiomers is a “racemic” mixture. The term “(±)” is used todesignate a racemic mixture where appropriate. “Diastereoisomers” or“diastereomers” are stereoisomers that have at least two asymmetricatoms but are not mirror images of each other. The absolutestereochemistry is specified according to the Cahn-Ingold-Prelog R-Ssystem. When a compound is a pure enantiomer, the stereochemistry ateach chiral carbon can be specified by either R or S. Resolved compoundswhose absolute configuration is unknown can be designated (+) or (−)depending on the direction (dextro- or levorotatory) in which theyrotate plane polarized light at the wavelength of the sodium D line.Certain compounds described herein contain one or more asymmetriccenters and can thus give rise to enantiomers, diastereomers, and otherstereoisomeric forms, the asymmetric centers of which can be defined, interms of absolute stereochemistry, as (R)- or (S)-. The present chemicalentities, pharmaceutical compositions and methods are meant to includeall such possible stereoisomers, including racemic mixtures, opticallypure forms, mixtures of diastereomers and intermediate mixtures.Optically active (R)- and (S)-isomers can be prepared using chiralsynthons or chiral reagents, or resolved using conventional techniques.The optical activity of a compound can be analyzed via any suitablemethod, including but not limited to chiral chromatography andpolarimetry, and the degree of predominance of one stereoisomer over theother isomer can be determined.

Chemical entities having carbon-carbon double bonds or carbon-nitrogendouble bonds may exist in Z- or E- form (or cis- or trans-form).Furthermore, some chemical entities may exist in various tautomericforms. Unless otherwise specified, chemical entities described hereinare intended to include all Z-, E- and tautomeric forms as well.

The term “substituted” refers to moieties having substituents replacinga hydrogen on one or more carbons or heteroatoms of the structure. Itwill be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, etc. As used herein, the term “substituted” iscontemplated to include all permissible substituents of organiccompounds. In a broad aspect, the permissible substituents includeacyclic and cyclic, branched and unbranched, carbocyclic andheterocyclic, aromatic and non-aromatic substituents of organiccompounds. The permissible substituents can be one or more and the sameor different for appropriate organic compounds. For purposes of thisdisclosure, the heteroatoms such as nitrogen may have hydrogensubstituents and/or any permissible substituents of organic compoundsdescribed herein which satisfy the valences of the heteroatoms.Substituents can include any substituents described herein, for example,a halogen, a hydroxyl, a carbonyl (such as a carboxyl, analkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as athioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, aphosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine,an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, asulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, aheterocyclyl, an aralkyl, a carbocycle, a heterocycle, a cycloalkyl, aheterocycloalkyl, an aromatic and heteroaromatic moiety. In someembodiments, substituents may include any substituents described herein,for example: halogen, hydroxy, oxo (═O), thioxo (=S), cyano (—CN), nitro(—NO₂), imino (═N—H), oximo (═N—OH), hydrazino (═N—NH₂), —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), — R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2); and alkyl, alkenyl,alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,and heteroarylalkyl any of which may be optionally substituted by alkyl,alkenyl, alkynyl, halogen, hydroxy, haloalkyl, haloalkenyl, haloalkynyl,oxo (═O), thioxo (═S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo(═N—OH), hydrazine (═N—NH₂), —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a),—R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂,—R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2);wherein each R^(a) is independently selected from hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each W,valence permitting, may be optionally substituted with alkyl, alkenyl,alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (═O), thioxo(═S), cyano (—CN), nitro (—NO₂), imino (═N—H), oximo (═N—OH), hydrazine(═N—NH₂), —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2); and wherein each R^(b) isindependently selected from a direct bond or a straight or branchedalkylene, alkenylene, or alkynylene chain, and each R_(c) is a straightor branched alkylene, alkenylene or alkynylene chain.

It will be understood by those skilled in the art that substituents canthemselves be substituted, if appropriate. Unless specifically stated as“unsubstituted,” references to chemical moieties herein are understoodto include substituted variants. For example, reference to a“heteroaryl” group or moiety implicitly includes both substituted andunsubstituted variants.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “salt” or “pharmaceutically acceptable salt” refers to saltsderived from a variety of organic and inorganic counter ions well knownin the art. Pharmaceutically acceptable acid addition salts can beformed with inorganic acids and organic acids. Inorganic acids fromwhich salts can be derived include, for example, hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. Organic acids from which salts can be derived include, forexample, acetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Pharmaceutically acceptable base additionsalts can be formed with inorganic and organic bases. Inorganic basesfrom which salts can be derived include, for example, sodium, potassium,lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese,aluminum, and the like. Organic bases from which salts can be derivedinclude, for example, primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines, basic ion exchange resins, and the like, specificallysuch as isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, and ethanolamine. In some embodiments, thepharmaceutically acceptable base addition salt is chosen from ammonium,potassium, sodium, calcium, and magnesium salts.

The term “effective amount” or “therapeutically effective amount” refersto that amount of a compound described herein that is sufficient toaffect the intended application, including but not limited to diseasetreatment, as defined below. The therapeutically effective amount mayvary depending upon the intended treatment application (in vivo), or thesubject and disease condition being treated, e.g., the weight and age ofthe subject, the severity of the disease condition, the manner ofadministration and the like, which can readily be determined by one ofordinary skill in the art. The term also applies to a dose that willinduce a particular response in target cells, e.g., reduction ofplatelet adhesion and/or cell migration. The specific dose will varydepending on the particular compounds chosen, the dosing regimen to befollowed, whether it is administered in combination with othercompounds, timing of administration, the tissue to which it isadministered, and the physical delivery system in which it is carried.

As used herein, “treatment” or “treating” refers to an approach forobtaining beneficial or desired results with respect to a disease,disorder, or medical condition including but not limited to atherapeutic benefit and/or a prophylactic benefit. By therapeuticbenefit is meant eradication or amelioration of the underlying disorderbeing treated. Also, a therapeutic benefit is achieved with theeradication or amelioration of one or more of the physiological symptomsassociated with the underlying disorder such that an improvement isobserved in the subject, notwithstanding that the subject may still beafflicted with the underlying disorder. In certain embodiments, forprophylactic benefit, the compositions are administered to a subject atrisk of developing a particular disease, or to a subject reporting oneor more of the physiological symptoms of a disease, even though adiagnosis of this disease may not have been made.

A “therapeutic effect,” as that term is used herein, encompasses atherapeutic benefit and/or a prophylactic benefit as described above. Aprophylactic effect includes delaying or eliminating the appearance of adisease or condition, delaying or eliminating the onset of symptoms of adisease or condition, slowing, halting, or reversing the progression ofa disease or condition, or any combination thereof

The term “co-administration,” “administered in combination with,” andtheir grammatical equivalents, as used herein, encompass administrationof two or more agents to an animal, including humans, so that bothagents and/or their metabolites are present in the subject at the sametime. Co-administration includes simultaneous administration in separatecompositions, administration at different times in separatecompositions, or administration in a composition in which both agentsare present.

The terms “antagonist” and “inhibitor” are used interchangeably, andthey refer to a compound having the ability to inhibit a biologicalfunction (e.g., activity, expression, binding, protein-proteininteraction) of a target protein (e.g., menin, MLL1, MLL2, and/or an MLLfusion protein). Accordingly, the terms “antagonist” and “inhibitor” aredefined in the context of the biological role of the target protein.While preferred antagonists herein specifically interact with (e.g.,bind to) the target, compounds that inhibit a biological activity of thetarget protein by interacting with other members of the signaltransduction pathway of which the target protein is a member are alsospecifically included within this definition. A preferred biologicalactivity inhibited by an antagonist is associated with the development,growth, or spread of a tumor.

The term “agonist” as used herein refers to a compound having theability to initiate or enhance a biological function of a targetprotein, whether by inhibiting the activity or expression of the targetprotein. Accordingly, the term “agonist” is defined in the context ofthe biological role of the target polypeptide. While preferred agonistsherein specifically interact with (e.g., bind to) the target, compoundsthat initiate or enhance a biological activity of the target polypeptideby interacting with other members of the signal transduction pathway ofwhich the target polypeptide is a member are also specifically includedwithin this definition.

“Signal transduction” is a process during which stimulatory orinhibitory signals are transmitted into and within a cell to elicit anintracellular response. A modulator of a signal transduction pathwayrefers to a compound which modulates the activity of one or morecellular proteins mapped to the same specific signal transductionpathway. A modulator may augment (agonist) or suppress (antagonist) theactivity of a signaling molecule.

An “anti-cancer agent”, “anti-tumor agent” or “chemotherapeutic agent”refers to any agent useful in the treatment of a neoplastic condition.One class of anti-cancer agents comprises chemotherapeutic agents.“Chemotherapy” means the administration of one or more chemotherapeuticdrugs and/or other agents to a cancer patient by various methods,including intravenous, oral, intramuscular, intraperitoneal,intravesical, subcutaneous, transdermal, buccal, or inhalation or in theform of a suppository.

“Subject” refers to an animal, such as a mammal, for example a human.The methods described herein can be useful in both human therapeuticsand veterinary applications. In some embodiments, the subject is amammal, and in some embodiments, the subject is human. “Mammal” includeshumans and both domestic animals such as laboratory animals andhousehold pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses,rabbits), and non-domestic animals such as wildlife and the like.

“Prodrug” is meant to indicate a compound that may be converted underphysiological conditions or by solvolysis to a biologically activecompound described herein (e.g., compound of Formula (I) or (II)). Thus,the term “prodrug” refers to a precursor of a biologically activecompound that is pharmaceutically acceptable. In some aspects, a prodrugis inactive when administered to a subject but is converted in vivo toan active compound, for example, by hydrolysis. The prodrug compoundoften offers advantages of solubility, tissue compatibility or delayedrelease in a mammalian organism (see, e.g., Bundgard, H., Design ofProdrugs (1985), pp. 7-9, 21-24 (Elsevier, Amsterdam); Higuchi, T., etal., “Pro-drugs as Novel Delivery Systems,” (1987) A.C.S. SymposiumSeries, Vol. 14; and Bioreversible Carriers in Drug Design, ed. EdwardB. Roche, American Pharmaceutical Association and Pergamon Press) eachof which is incorporated in full by reference herein. The term “prodrug”is also meant to include any covalently bonded carriers, which releasethe active compound in vivo when such prodrug is administered to amammalian subject. Prodrugs of an active compound, as described herein,are typically prepared by modifying functional groups present in theactive compound in such a way that the modifications are cleaved, eitherin routine manipulation or in vivo, to the parent active compound.Prodrugs include compounds wherein a hydroxy, amino or mercapto group isbonded to any group that, when the prodrug of the active compound isadministered to a mammalian subject, cleaves to form a free hydroxy,free amino or free mercapto group, respectively. Examples of prodrugsinclude, but are not limited to, acetate, formate and benzoatederivatives of a hydroxy functional group, or acetamide, formamide andbenzamide derivatives of an amine functional group in the activecompound and the like.

The term “in vivo” refers to an event that takes place in a subject'sbody.

The term “in vitro” refers to an event that takes places outside of asubject's body. For example, an in vitro assay encompasses any assay runoutside of a subject. In vitro assays encompass cell-based assays inwhich cells alive or dead are employed. In vitro assays also encompass acell-free assay in which no intact cells are employed.

“Optional” or “optionally” means that the subsequently described eventof circumstances may or may not occur, and that the description includesinstances where the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl group may or may not be substituted and that the descriptionincludes both substituted aryl groups and aryl groups having nosubstitution.

“Pharmaceutically acceptable carrier, diluent or excipient” includeswithout limitation any adjuvant, carrier, excipient, glidant, sweeteningagent, diluent, preservative, dye, colorant, flavor enhancer,surfactant, wetting agent, dispersing agent, suspending agent,stabilizer, isotonic agent, solvent, or emulsifier which has beenapproved by the United States Food and Drug Administration as beingacceptable for use in humans or domestic animals.

The present disclosure provides compounds for modulating the interactionof menin with proteins such as MLL1, MLL2 and MLL-fusion oncoproteins.In certain embodiments, the disclosure provides compounds and methodsfor inhibiting the interaction of menin with its upstream or downstreamsignaling molecules including but not limited to MLL1, MLL2 andMLL-fusion oncoproteins. Compounds of the disclosure may be used inmethods for the treatment of a wide variety of cancers and otherdiseases associated with one or more of MLL1, MLL2, MLL fusion proteins,and menin. In certain embodiments, a compound of the disclosurecovalently binds menin and inhibits the interaction of menin with MLL.In certain embodiments, a compound of the disclosure interactsnon-covalently with menin and inhibits the interaction of menin withMLL.

Compounds of the disclosure may be used in methods for treating a widevariety of diseases associated with MLL1, MLL2, MLL fusion proteins, andmenin. In certain embodiments, a compound of the disclosure interactsnon-covalently with menin and inhibits the interaction of menin withMLL. In certain embodiments, a compound of the disclosure covalentlybinds menin and inhibits the interaction of menin with MLL.

In some aspects, the present disclosure provides a compound or salt thatselectively binds to the menin protein and/or modulates the interactionof menin with an MLL protein (e.g., MLL 1, MLL2, or an MLL fusionprotein). In certain embodiments, the compound modulates the meninprotein by binding to or interacting with one or more amino acids and/orone or more metal ions. Certain compounds may occupy the F9 and/or P13pocket of menin. The binding of a compound disclosed herein may disruptmenin or MLL (e.g., MLL1, MLL2, or an MLL fusion protein) downstreamsignaling.

In certain aspects, the present disclosure provides a compound ofFormula (I):

or a pharmaceutically acceptable salt, isotopic form, or prodrugthereof, wherein:

H is selected from C₅₋₁₂ carbocycle and 5- to 12-membered heterocycle,each of which is optionally substituted with one or more R⁵⁰;

A is selected from bond, C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle;

B is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

C is 3- to 12-membered heterocycle;

L¹, L² and L³ are each independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰, wherein two R⁵⁰ groups attached to thesame atom or different atoms of any one of L¹, L² or L³ can togetheroptionally form a bridge or ring;

R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups or two R^(C)groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

m, n and p are each independently an integer from 0 to 6;

R⁵⁰ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;        and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)²,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   halogen, —NO₂, —CN, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵⁸,        —S(═O)₂N(R⁵²)₂, ——S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)OR⁵², —OC(O)R⁵²,        —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)OR⁵²,        ——NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl ),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═S, ═N(R⁵²); and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —NO₂, —CN, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,        —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,        —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═S, and ═N(R⁵²);        and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle,

wherein for a compound or salt of Formula (I), when C is azetidinylene,piperidinylene or piperazinylene and R⁵⁷ is —S(—50 O)₂R⁵⁸,—S(═O)₂N(R⁵²)₂, or —NR⁵²S(═O)₂R⁵²:

p is an integer from 1 to 6; and/or

L³ is substituted with one or more R⁵⁰, wherein L³ is not —CH₂CH(OH)—.

In certain aspects, the present disclosure provides a compound ofFormula (II):

or a pharmaceutically acceptable salt thereof, wherein:

H is selected from C₅₋₁₂ carbocycle and 5- to 12-membered heterocycle,each of which is optionally substituted with one or more R⁵⁰;

A, B and C are each independently selected from C₃₋₁₂ carbocycle and 3-to 12-membered heterocycle;

L¹ and L² are each independently selected from bond, —O—, —S—, —N(R⁵¹)—,—N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰;

L³ is selected from alkylene, alkenylene, and alkynylene, each of whichis substituted with one or more R⁵⁶ and optionally further substitutedwith one or more R⁵⁰;

R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups or two R^(C)_(g)roups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

m, n and p are each independently an integer from 0 to 6;

R⁵⁰ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;        and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁶ is independently selected at each occurrence from:

-   -   —NO₂, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₁₀ alkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle and 3- to 12-membered        heterocycle,    -   wherein each C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl in        R⁵⁶ is independently optionally substituted at each occurrence        with one or more substituents selected from halogen, —NO₂, —CN,        —OR⁵⁹, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁶ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)²,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², - NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and    -   further wherein R⁵⁶ optionally forms a bond to ring C; and

R⁵⁹ is independently selected at each occurrence from C₁₋₂₀ alkyl, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle,and 3- to 12-membered heterocycle, each of which is optionallysubstituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH,—OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle,

wherein for a compound or salt of Formula (II), when R⁵⁶ is —CH₃, L³ isnot further substituted with —OH, —NH₂, or —CN.

In certain aspects, the present disclosure provides a compound ofFormula (I):

or a pharmaceutically acceptable salt, isotopic form, or prodrugthereof, wherein:

H is selected from C5_12 carbocycle and 5- to 12-membered heterocycle,each of which is optionally substituted with one or more R⁵⁰;

A is selected from bond, C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle;

B is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

C is 3- to 12-membered heterocycle;

L¹, L² and L³ are each independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂₀—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰, wherein two R⁵⁰ groups attached to thesame atom or different atoms of any one of L¹, L² or L³ can togetheroptionally form a bridge or ring;

R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups or two R^(C)groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

m, n and p are each independently an integer from 0 to 6;

R⁵⁰ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle, and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)²,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   halogen, —NO₂, —CN, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵⁸,        —S(═O)₂N(R⁵²)₂, ——S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)OR⁵², —OC(O)R⁵²,        —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, ═N(R⁵²); and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —NO₂, —CN, ——SR⁵², —N(R⁵²)₂,        —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,        —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)²,        —NR⁵²C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²),        —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²),        —P(O)(NR⁵²)₂, ═S, and ═N(R⁵²); and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alky, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- and 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle,

wherein for a compound or salt of Formula (I), when C is azetidinylene,piperidinylene or piperazinylene and R⁵⁷ is —S(—50 O)₂R⁵⁸,—S(═O)₂N(R⁵²)₂, or —NR⁵²S(═O)₂R⁵²:

p is an integer from 1 to 6; and/or

L³ is substituted with one or more R⁵⁰, wherein L³ is not —CH₂CH(OH)—.

In certain aspects, the present disclosure provides a compound ofFormula (II):

or a pharmaceutically acceptable salt thereof, wherein:

H is selected from C5_12 carbocycle and 5- to 12-membered heterocycle,each of which is optionally substituted with one or more R⁵⁰;

A, B and C are each independently selected from C₃₋₁₂ carbocycle and 3-to 12-membered heterocycle;

L¹ and L² are each independently selected from bond, —O—, —S—, —N(R⁵¹)—,—N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂O—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰;

L³ is selected from alkylene, alkenylene, and alkynylene, each of whichis substituted with one or more R⁵⁶ and optionally further substitutedwith one or more R⁵⁰;

R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups or two R^(C)_(g)roups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

m, n and p are each independently an integer from 0 to 6;

R⁵⁰ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle, and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂,═O, ═S, ═N(R⁵²),        C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂,═O, ═S, ═N(R⁵²),        C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁶ is independently selected at each occurrence from:

-   -   —NO₂, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂        carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl in        R⁵⁶ is independently optionally substituted at each occurrence        with one or more substituents selected from halogen, —NO₂, —CN,        —OR⁵⁹, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,        —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²), —NR⁵²P(O)(R⁵²),        —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂,═O, ═S, ═N(R⁵²), C₃₋₁₂        carbocycle, and 3- to 12-membered heterocycle;    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁶ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)²,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, —P(O)(OR⁵²)(R⁵²), —P(O)(NR⁵²)(R⁵²),        —NR⁵²P(O)(R⁵²), —P(O)(NR⁵²)(OR⁵²), —P(O)(NR⁵²)₂, ═O, ═S,        ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆        alkynyl; and    -   further wherein R⁵⁶ optionally forms a bond to ring C; and

R⁵⁹ is independently selected at each occurrence from C₁₋₂₀ alkyl, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle,and 3- to 12-membered heterocycle, each of which is optionallysubstituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH,—OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle,

wherein for a compound or salt of Formula (II), when R⁵⁶ is —CH₃, L³ isnot further substituted with —OH, —NH₂, or —CN.

In some embodiments, for a compound of Formula (I) or (II), H is 5- to12-membered heterocycle, such as 6- to 12-membered bicyclic heterocycle,optionally substituted with one or more R⁵⁰. In some embodiments, Hcontains one or more heteroatoms, such as 1, 2, 3, 4, 5 or 6 ringheteroatoms. In some embodiments, H contains at least 1, 2, 3, 4 or 5ring nitrogen atoms. In some embodiments, H is thienopyrimidinyl,optionally substituted with one or more R⁵⁰. In some embodiments, H issubstituted with C₁₋₄ haloalkyl, such as —CH₂CF₃. In some embodiments, His substituted with one or more R⁵⁰ (e.g., by replacing a hydrogenconnected to a ring atom with a bond to R⁵⁰). H may be substituted with0, 1, 2, 3, 4, 5, 6 or more R⁵⁰ groups. H may be substituted with 1, 2,3, 4, 5 or 6 R⁵⁰ groups, such as H substituted with 1 or 2 R⁵⁰ groups.In some embodiments, H is substituted with at least 1, 2, 3, 4, 5 or 6R⁵⁰ groups. In some embodiments, H is substituted with up to 6, 5, 4, 3,2 or 1 R⁵⁰ groups.

In some embodiments, for a compound of Formula (I) or (II), H is

wherein X¹ and X² are each independently selected from CR² and N; X³ andX⁴ are each independently selected from C and N; Y¹ and Y² are eachindependently selected from CR³, N, NR⁴, O, and S; R¹, R² and R³ areeach independently selected at each occurrence from hydrogen and R⁵⁰;and R⁴ is selected from R⁵¹. In some embodiments, X³ and X⁴ are each C.In some embodiments, X¹ is CR², and R² is selected from hydrogen,halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵²,—CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl,and C₂₋₃ alkynyl, such as R² is selected from —OH, —OR⁵², —NH₂,—N(R⁵²)₂, —CN, and C₁₋₂ alkyl. In some embodiments, R² is methyl or—NHCH₃. In some embodiments, R² is H. In some embodiments, X² is N. Insome embodiments, Y² is CR³, and R³ is selected from hydrogen, halogen,—OH, —N(R⁵²)₂, —CN, —C(O)OR⁵², C₁₋₃ alkyl, and C₁₋₃ haloalkyl. In someembodiments, Y¹ is S. In some embodiments, at least one of Y¹ and Y² isselected from N, NR⁴, O and S. In some embodiments, R¹ is C₁₋₃haloalkyl, such as —CH₂CF3. In some embodiments, X¹ is CR², X² is N, X³and X⁴ are each C, Y¹ is S, Y² is CR³, and R¹ is selected from R⁵⁰. Insome embodiments, X¹ is CR²; X² is N; X³ and X⁴ are each C; Y¹ is S; Y²is CH; R¹ is C₁₋₃ haloalkyl; and R² is selected from hydrogen, halogen,—OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵², —CH₂NH₂,—CH₂N(R⁵²)₂, C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃alkynyl. In some embodiments, H is

In some embodiments, H is

such as

In some embodiments, H is

and R² is selected from hydrogen, halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂,—CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵², —CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl. In someembodiments, R² is selected from hydrogen, halogen, —OH, alkoxy (e.g.,—OR⁵², —OCH₃, —OCH₂CH₃), aminoalkyl, alkylamino, —N(R⁵²)₂ (e.g., —NH₂,—NHCH₃, —NHCH₂CH₃), —N(CH₃)₂, —CN, C₁₋₃ alkyl (e.g., —CH₃), cyclopropyl,C₁₋₃ alkyl-OR⁵² (e.g., —CH₂OH, —CH₂OC(O)CH₃), C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl.

In some embodiments, for a compound of Formula (I) or (II), H is

wherein R¹ is selected from H, halo, hydroxyl, amino, cyano,dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl,heteroalkyl, and haloalkyl, such as from alkyl and haloalkyl; R² isselected from H, halo, hydroxyl, amino, cyano, dialkylphosphine oxide,oxo, carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl,aminoalkyl, hydroxyalkyl, alkoxy, and alkylamino, such as from H, halo,hydroxyl, and amino; and each of Y¹ and Y² is independently selectedfrom S, CR³, N, NR⁴ and O. In certain embodiments, up to one of Y¹ andY² is O or S.

In some embodiments, for a compound of Formula (I) or (II), L¹ comprisesless than 20 atoms, such as less than 10 atoms. In some embodiments, L¹comprises less than 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms.In some embodiments, L¹ comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 15 or at least 20 atoms. In some embodiments, L¹ comprises at leastone heteroatom, such as L¹ comprises at least one nitrogen. In someembodiments, L¹ is substituted with one or more R⁵⁰. In someembodiments, L¹ is unsubstituted. In some embodiments, L¹ is selectedfrom bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—,—C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—, —S(O)—,—N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, alkylene, alkenylene,heteroalkylene, and heteroalkenylene. In some embodiments, L¹ isselected from bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—,—OC(O)—, —C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—,—S(O)—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, C₁₋₆ alkyleneand C₂₋₆ alkenylene, wherein the C₁₋₆ alkylene and C₂₋₆ alkenylene areeach optionally substituted with one or more R⁵⁰. In some embodiments,L¹ is —N(R⁵¹)—, such as —NH—. In some embodiments, L¹ is selected from—O—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, N(R⁵¹)CH₂—, —C(O)—, —C(O)N(R⁵¹)—,—N(R⁵¹)C(O)—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, C₁₋₄ alkylene, C₂₋₄alkenylene, and C₁₋₄ heteroalkylene. In some embodiments, L¹ is—N(R⁵¹)—, wherein R⁵¹ is selected from hydrogen and alkyl.

In some embodiments, for a compound of Formula (I) or (II), A is 3- to12-membered heterocycle, such as 5- to 8-membered heterocycle. In someembodiments, A is 6-membered monocyclic heterocycle. In someembodiments, the heterocycle comprises at least one nitrogen atom. Insome embodiments, A comprises at least one ring nitrogen. In someembodiments, A is selected from piperidinylene and piperazinylene, suchas

In some embodiments, A is

In some embodiments, A is an aromatic, non-aromatic, saturated orunsaturated ring. In some embodiments, A is selected from arylene,cycloalkylene, heterocycloalkylene, N-heterocycloalkylene,heteroarylene, and N-heteroarylene. In some embodiments, A is 5- to8-membered heterocycle, wherein the heterocycle comprises at least 1, 2,3 or 4 ring heteroatoms selected from N, O and S.

In some embodiments, A is selected from

In some embodiments, A is substituted with one or more R^(A) (e.g., byreplacing a hydrogen connected to a ring atom with a bond to R^(A)). Amay be substituted with 0, 1, 2, 3, 4, 5, 6 or more R^(A) groups. A maybe substituted with 1, 2, 3, 4, 5 or 6 R^(A) groups, such as Asubstituted with 1 or 2 R^(A) groups. In some embodiments, A issubstituted with at least 1, 2, 3, 4, 5 or 6 R^(A) groups. In someembodiments, A is unsubstituted. In some embodiments, A is substitutedwith m R^(A) groups, wherein m is an integer from 0 to 6. In someembodiments, m is 0, 1, 2, 3, 4, 5 or 6. In some embodiments, m is atleast 1, 2, 3, 4, 5 or 6. In some embodiments, m is up to 6, 5, 4, 3, 2,or 1. In some embodiments, m is 0.

In some embodiments, R^(A) is independently selected at each occurrencefrom halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo,carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl,aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl,cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino,cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy,heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl,aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl,heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, andheteroarylalkylamino In some embodiments, two R^(A) groups attached tothe same atom or different atoms can together form a ring.

In some embodiments, for a compound of Formula (I) or (II), L² comprisesless than 20 atoms, such as less than 10 atoms. In some embodiments, L²comprises less than 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3 atoms.In some embodiments, L² comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 15 or at least 20 atoms. In some embodiments, L² comprises at leastone heteroatom, such as L² comprises at least one nitrogen. In someembodiments, L² is C₁₋₁₀ alkylene, such as C₁₋₄ alkylene, optionallysubstituted with one or more R⁵⁰. In some embodiments, L² is substitutedwith one or more R⁵⁰. In some embodiments, L² is unsubstituted. In someembodiments, L² is selected from bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—, —S(O)—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)₂N(R⁵¹)—, alkylene, alkenylene, heteroalkylene, andheteroalkenylene. In some embodiments, L² is selected from bond, —O—,—S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R⁵¹)—,—N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—, —S(O)—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, C₁₋₆ alkylene and C₂₋₆ alkenylene,wherein the C₁₋₆ alkylene and C₂₋₆ alkenylene are each optionallysubstituted with one or more R⁵⁰. In some embodiments, L² is selectedfrom —O—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, C₁₋₄ alkylene and C₁₋₄ heteroalkylene. Insome embodiments, L² is selected from —CH₂—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—N(R⁵¹)C(O)—, and —N(R⁵¹)S(O)₂—. In some embodiments, L² is —CH₂—.

In some embodiments, for a compound of Formula (I) or (II), B is 3- to12-membered heterocycle, such as 6- to 12-membered bicyclic heterocycle.In some embodiments, the heterocycle comprises at least one nitrogenatom. In some embodiments, B is 6- to 12-membered heterocycle, whereinthe heterocycle comprises at least 1, 2, 3 or 4 ring heteroatomsselected from N, O and S. In some embodiments, B is a 6,5- or6,6-bicyclic heterocycle. In some embodiments, B comprises at least onering nitrogen. In some embodiments, B is indolylene, such as

optionally substituted with one or more R^(B). In some embodiments, B is

such as

In some embodiments, B is selected from

wherein Z¹, Z², Z³ and Z⁴ are each independently selected from CR⁷, Nand NR⁹; Z⁵ is selected from C and N; Z⁶, Z⁷ and Z⁸ are eachindependently selected from CR⁸, N, NR⁹, O and S; Z⁹, Z¹⁰ and Z¹¹ areeach independently selected from CR¹⁰, CR¹¹R¹², N¹³, O and S; R⁷, R⁸,R¹⁰, R¹¹, and R¹² are each independently selected from hydrogen and R⁵⁰;and R⁹ and R¹³ are each independently selected from R⁵¹, wherein B maybe connected at any ring atom to L² or L³ (e.g., by replacing a hydrogenconnected to a ring atom with a bond to L² or L³).

In some embodiments, B is selected from

In some embodiments, B is substituted with one or more R^(B) (e.g., byreplacing a hydrogen connected to a ring atom with a bond to R^(B) ). Bmay be substituted with 0, 1, 2, 3, 4, 5, 6 or more R^(B) groups. B maybe substituted with 1, 2, 3, 4, 5 or 6 R^(B) groups, such as Bsubstituted with 1 or 2 R^(B) groups. In some embodiments, B issubstituted with at least 1, 2, 3, 4, 5 or 6 R^(B) groups. In someembodiments, B is substituted with n R^(B) groups, wherein n is aninteger from 0 to 6. In some embodiments, n is 0, 1, 2, 3, 4, 5 or 6. Insome embodiments, n is at least 1, 2, 3, 4, 5 or 6. In some embodiments,n is up to 6, 5, 4, 3, 2, or 1. In some embodiments, n is an integerfrom 1 to 3.

In some embodiments, R^(B) is independently selected at each occurrencefrom halo, hydroxyl, amino, cyano, dialkylphosphine oxide, oxo,carboxyl, amido, acyl, alkyl, cycloalkyl, heteroalkyl, haloalkyl,aminoalkyl, hydroxyalkyl, alkoxy, alkylamino, cycloalkylalkyl,cycloalkyloxy, cycloalkylalkyloxy, cycloalkylamino,cycloalkylalkylamino, heterocyclyl, heterocyclylalkyl, heterocyclyloxy,heterocyclylalkyloxy, heterocyclylamino, heterocyclylalkylamino, aryl,aralkyl, aryloxy, aralkyloxy, arylamino, aralkylamino, heteroaryl,heteroarylalkyl, heteroaryloxy, heteroarylalkyloxy, heteroarylamino, andheteroarylalkylamino In some embodiments, R^(B) is independentlyselected at each occurrence from halo, hydroxyl, amino, cyano,dialkylphosphine oxide, oxo, carboxyl, amido, acyl, alkyl, cycloalkyl,heteroalkyl, haloalkyl, aminoalkyl, hydroxyalkyl, alkoxy, alkylamino,heterocyclylalkyl, and heteroarylalkyl. In some embodiments, two R^(B)groups attached to the same atom or different atoms can together form aring.

In some embodiments, for a compound of Formula (I), L³ comprises lessthan 30 atoms, such as less than 20 atoms. In some embodiments, L³comprises less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3atoms. In some embodiments, L³ comprises at least 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 15 or at least 20 atoms. In some embodiments, L³ comprises atleast one heteroatom, such as L³ comprises at least one nitrogen. Insome embodiments, L³ is C₁₋₁₀ alkylene, such as C₁₋₄ alkylene,optionally substituted with one or more R⁵⁰. In some embodiments, L³ issubstituted with one or more R⁵⁰. In some embodiments, L³ isunsubstituted. In some embodiments, L³ is selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R⁵¹)—,—N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—, —S(O)—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, alkylene, alkenylene,heteroalkylene, and heteroalkenylene. In some embodiments, L³ is C₁₋₆alkylene, optionally substituted with one or more R⁵⁰, wherein R⁵⁰ isselected from deuterium, C₁₋₄ alkyl, C₁₋₄₀ haloalkyl, and —OR⁵². In someembodiments, L³ is —CH₂CH(R⁵⁰)—, such as —CH₂CH(CH₃)—. In someembodiments, two R⁵⁰ groups attached to the same atom or different atomsof L³ optionally form a bridge or ring, such as a cyclopropyl ring. Insome embodiments, L³ is substituted with R⁵⁰, wherein R⁵⁰ forms a bondto ring C. In some embodiments, L³ is substituted with one or moregroups selected from deuterium, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and —OR⁵².In some embodiments, L³ is substituted with —CH₃. In some embodiments,L³ is C₂ alkylene substituted with at least one C₁₋₃ alkyl or C₁₋₃haloalkyl, and optionally further substituted with one or more R⁵⁰. Insome embodiments, L³ is substituted with ═O, C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₁₋₃ alkyl(cyclopropyl), C₁₋₃ alkyl(NR⁵²C(O)R⁵²) or —O(C₁₋₆ alkyl).

In some embodiments, for a compound of Formula (I), L³ is selected from

Optionally, R⁵⁰ is methyl. L³ may be selected from

In some embodiments, L³ is

In some embodiments, L³ is

In some embodiments, L³ comprises a stereocenter. In some embodiments,the stereocenter is in the R-configuration. In some embodiments, thestereocenter is in the S-configuration. In some embodiments, theR-isomer of L³ is provided in at least 20%, 30%, 40%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99%, 99.5%, or 99.9% excess over the S-isomer. In some embodiments,the S-isomer of L³ is provided in at least 20%, 30%, 40%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99%, 99.5%, or 99.9% excess over the R-isomer.

In some embodiments, for a compound of Formula (I), C is azetidinylene,piperidinylene or piperazinylene; R⁵⁷ is —S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,or —NR⁵²S(═O)₂R⁵²; and L³ is substituted with one or more R⁵⁰, whereinL³ is not —CH₂CH(OH)—. In some embodiments, C is azetidinylene,piperidinylene or piperazinylene; R⁵⁷ is —S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,or —NR⁵²S(═O)₂R⁵²; and L³ is substituted with C₁₋₄ alkyl or C₁₋₄haloalkyl.

In some embodiments, for a compound of Formula (I), L³ is selected from

and any combination thereof. In some embodiments, for a compound ofFormula (I), L³ is selected from

In some embodiments, for a compound of Formula (II), L³ comprises lessthan 30 atoms, such as less than 20 atoms. In some embodiments, L³comprises less than 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, or less than 3atoms. In some embodiments, L³ comprises at least 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 15 or at least 20 atoms. In some embodiments, L³ is C₁₋₁₀alkylene, such as C₁₋₄ alkylene, substituted with one or more R⁵⁶ andoptionally further substituted with one or more R⁵⁰. In someembodiments, L³ is substituted with one or more R⁵⁰. In someembodiments, L³ is substituted with R⁵⁶. In some embodiments, L³ isselected from alkylene and alkenylene. In some embodiments, L³ is C₁₋₆alkylene substituted with one or more R⁵⁶, wherein R⁵⁶ is selected fromdeuterium, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and —OR⁵⁹. In some embodiments,L³ is C₁₋₄ alkylene substituted with R⁵⁶, wherein R⁵⁶ forms a bond toring C. In some embodiments, L³ is —CH₂CH(R⁵⁶)—, such as —CH₂CH(CH₃)—.In some embodiments, two R⁵⁶ groups attached to the same atom ordifferent atoms of L³ optionally form a bridge or ring, such as acyclopropyl ring. In some embodiments, L³ is substituted with R⁵⁶,wherein R⁵⁶ forms a bond to ring C. In some embodiments, L³ issubstituted with one or more groups selected from C₁₋₄ alkyl, C₁₋₄haloalkyl, and —OR⁵⁹. In some embodiments, L³ is substituted with —CH₃.In some embodiments, L³ is C₁₋₄ alkylene substituted with —CH₃ andoptionally further substituted with R⁵⁰, wherein R⁵⁰ is not —OH, —NH₂,or —CN. In some embodiments, L³ is C₂ alkylene substituted with at leastone C₁₋₃ alkyl or C₁₋₃ haloalkyl, and optionally further substitutedwith one or more R⁵⁰. In some embodiments, L³ is substituted with ═O,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₃ alkyl(cyclopropyl), C₁₋₃alkyl(NR⁵²C(O)R⁵²) or —O(C₁₋₆ alkyl).

In some embodiments, for a compound of Formula (II), L³ is selected from

Optionally, R⁵⁶ is methyl. L³ may be selected from

In some embodiments, L³ is

In some embodiments, L³ is

In some embodiments, L³ comprises a stereocenter. In some embodiments,the stereocenter is in the R-configuration. In some embodiments, thestereocenter is in the S-configuration. In some embodiments, theR-isomer of L³ is provided in at least 20%, 30%, 40%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99%, 99.5%, or 99.9% excess over the S-isomer. In some embodiments,the S-isomer of L³ is provided in at least 20%, 30%, 40%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99%, 99.5%, or 99.9% excess over the R-isomer.

In some embodiments, for a compound of Formula (II), L³ is selected from

and any combination thereof. In some embodiments, for a compound ofFormula (II), L³ is selected from

In some embodiments, for a compound of Formula (I), C is 3- to12-membered heterocycle, such as 5- to 12-membered heterocycle. In someembodiments, the heterocycle is saturated. In some embodiments, C isselected from 5- to 7-membered monocyclic heterocycle, 8- to 10-memberedfused bicyclic heterocycle, and 7- to 12-membered spirocyclicheterocycle. In some embodiments, the heterocycle comprises at least onenitrogen atom, such as one or two nitrogen atoms. In some embodiments, Ccomprises at least one ring nitrogen. In some embodiments, C is selectedfrom piperidinyl and piperazinyl, such as

In some embodiments, C is selected from

In some embodiments, C is selected from

In some embodiments, C is selected from

optionally substituted with one or more R^(C). In some embodiments, C isselected from

wherein R⁵⁷ is selected from —S(—50 O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²; and C₁₋₁₀ alkyl substituted with one ormore substituents selected from —S(—50 O)R⁵², —S(═O)₂R⁵²,—S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, and —NR⁵²S(═O)₂R⁵². In some embodiments,R⁵⁷ is selected from —S(—50 O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and—NR⁵²S(═O)₂R⁵², such as R⁵⁷ is selected from —S(—50 O)CH₃, —S(═O)₂CH₃,—S(═O)₂NH₂, —NHS(═O)₂CH₃, and —S(—50 O)₂NHCH₃.

In some embodiments, for a compound of Formula (I), C is selected from

In some embodiments, for a compound of Formula (I), R⁵⁷ is selected from—S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),—C(O)NR⁵³R⁵⁴; and C₁₋₆ alkyl and C₂₋₆ alkenyl, each of which isindependently substituted at each occurrence with one or moresubstituents selected from —S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selectedfrom —S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, and C₁₋₆ alkyl substituted withone or more substituents selected from —S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, and—NR⁵²S(═O)₂NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selected from —S(—50O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵². In someembodiments, R⁵⁷ is selected from —S(—50 O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂,—NHS(═O)₂CH₃, and —S(—50 O)₂NHCH₃.

In some embodiments, for a compound of Formula (I) or (II), C issubstituted with one or more R^(C) (e.g., by replacing a hydrogenconnected to a ring atom with a bond to R^(C) ). C may be substitutedwith 0, 1, 2, 3, 4, 5, 6 or more R^(C) groups. C may be substituted with1, 2, 3, 4, 5 or 6 R^(C) groups, such as C substituted with 1 or 2 R^(C)groups. In some embodiments, C is substituted with at least 1, 2, 3, 4,5 or 6 R^(C) groups. In some embodiments, C is unsubstituted. In someembodiments, C is substituted with p R^(C) groups, wherein p is aninteger from 0 to 6. In some embodiments, p is 0, 1, 2, 3, 4, 5 or 6. Insome embodiments, p is at least 1, 2, 3, 4, 5 or 6. In some embodiments,p is up to 6, 5, 4, 3, 2, or 1. In some embodiments, p is 0. In someembodiments, p is 1 or 2. In some embodiments, for a compound of Formula(I), C is azetidinylene, piperidinylene or piperazinylene; R⁵⁷ is —S(—50O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, or —NR⁵²S(═O)₂R⁵²; and p is an integer from 1 to6.

In some embodiments, R^(C) is selected from —C(O)R⁵², —S(═O)R⁵²,—S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², ═O, C₁₋₃alkyl, and C₁₋₃ haloalkyl, or two R^(C) groups attached to differentatoms can together form a C₁₋₃ bridge. In some embodiments, R^(C) isselected from C₁₋₃ alkyl and C₁₋₃ haloalkyl, such as —CH₃.

In some embodiments, for a compound of Formula (II), C is selected fromC₃₋₁₂ carbocycle and 3- to 12-membered heterocycle, such as 5- to12-membered heterocycle. In some embodiments, the heterocycle issaturated. In some embodiments, C is selected from 5- to 7-memberedmonocyclic heterocycle, 8- to 10-membered fused bicyclic heterocycle,and 7- to 12-membered spirocyclic heterocycle. In some embodiments, theheterocycle comprises at least one nitrogen atom, such as one or twonitrogen atoms. In some embodiments, C comprises at least one ringnitrogen. In some embodiments, C is selected from piperidinyl andpiperazinyl, such as

wherein R⁵⁷ is selected from hydrogen and R⁵⁰. In some embodiments, C isselected from

wherein R⁵⁷ is selected from hydrogen and R⁵⁰. In some embodiments, C isselected from

wherein R⁵⁷ is selected from hydrogen and R⁵⁰. In some embodiments, C isselected from

optionally substituted with one or more R^(C), wherein R⁵⁷ is selectedfrom hydrogen and R⁵⁰ In some embodiments, C is selected from

wherein R⁵⁷ is selected from —S(—50 O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²; and C₁₋₁₀ alkyl substituted with one ormore substituents selected from —S(—50 O)R⁵², —S(═O)₂R⁵²,—S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, and —NR⁵²S(═O)₂R⁵². In some embodiments,R⁵⁷ is selected from —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, and—NR⁵²S(═O)₂R⁵², such as R⁵⁷ is selected from —S(—50 O)CH₃, —S(═O)₂CH₃,—S(═O)₂NH₂, —NHS(═O)₂CH₃, and —S(—50 O)₂NHCH₃.

In some embodiments, for a compound of Formula (II), C is selected from

In some embodiments, for a compound of Formula (I) or (II), R^(C) isselected from:

-   -   halogen, —OR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂; and

C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂,—NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵²,—C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,—NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,—C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²),C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;

wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle in R^(C)is independently optionally substituted with one or more substituentsselected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,—S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, and —C(O)NR⁵³R⁵⁴. Insome embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, C₁₋₆alkyl, and C₁₋₆ alkyl substituted with —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, or —C(O)NR⁵³R⁵⁴.

In some embodiments, C is selected from

In some embodiments, for a compound of Formula (I) or (II), H is 5- to12-membered heterocycle, optionally substituted with one or more R⁵⁰; Ais 3- to 12-membered heterocycle; and B is 3- to 12-memberedheterocycle. In some embodiments, H is 6- to 12-membered bicyclicheterocycle, optionally substituted with one or more R⁵⁰; A is 3- to12-membered heterocycle; and B is 3- to 12-membered heterocycle. In someembodiments, H is 6- to 12-membered bicyclic heterocycle, optionallysubstituted with one or more R⁵⁰; A is 3- to 12-membered heterocycle;and B is 6- to 12-membered bicyclic heterocycle. In some embodiments, His 5- to 12-membered heterocycle, optionally substituted with one ormore R⁵⁰; A is 3- to 12-membered heterocycle; and B is 6- to 12-memberedbicyclic heterocycle. In some embodiments, H is thienopyrimidinyl,optionally substituted with one or more R⁵⁰; A is 3- to 12-memberedheterocycle; and B is 3- to 12-membered heterocycle. In someembodiments, H is 5- to 12-membered heterocycle, optionally substitutedwith one or more R⁵⁰; A is selected from piperidinylene andpiperazinylene; and B is 3- to 12-membered heterocycle. In someembodiments, H is 5- to 12-membered heterocycle, optionally substitutedwith one or more R⁵⁰; A is 3- to 12-membered heterocycle; and B isindolylene. In some embodiments, H is thienopyrimidinyl substituted withone or more R⁵⁰; A is selected from piperidinylene and piperazinylene;and B is indolylene.

In some embodiments, for a compound of Formula (I) or (II), H is 5- to12-membered heterocycle, optionally substituted with one or more R⁵⁰; Ais 3- to 12-membered heterocycle; B is 3- to 12-membered heterocycle; Cis 3- to 12-membered heterocycle; m is an integer from 0 to 3; and n isan integer from 1 to 3. In some embodiments, H is 6- to 12-memberedbicyclic heterocycle, optionally substituted with one or more R⁵⁰; A is3- to 12-membered heterocycle; B is 6- to 12-membered bicyclicheterocycle; C is 3- to 12-membered heterocycle; m is an integer from 0to 3; and n is an integer from 1 to 3. In some embodiments, H is 5- to12-membered heterocycle, optionally substituted with one or more R⁵⁰; Ais 3- to 12-membered heterocycle; B is 3- to 12-membered heterocycle;and C is 3- to 12-membered heterocycle. In some embodiments, H is 6- to12-membered bicyclic heterocycle, optionally substituted with one ormore R⁵⁰; A is 3- to 12-membered heterocycle; B is 6- to 12-memberedbicyclic heterocycle; and C is 3- to 12-membered heterocycle. In someembodiments, H is 6- to 12-membered bicyclic heterocycle, optionallysubstituted with one or more R⁵⁰; A is selected from piperidinylene andpiperazinylene; B is 6- to 12-membered bicyclic heterocycle; and C is 3-to 12-membered heterocycle. In some embodiments, H is 6- to 12-memberedbicyclic heterocycle, optionally substituted with one or more R⁵⁰; A isselected from piperidinylene and piperazinylene; B is 6- to 12-memberedbicyclic heterocycle; m is an integer from 0 to 3; and n is an integerfrom 1 to 3. In some embodiments, H is thienopyrimidinyl, optionallysubstituted with one or more R⁵⁰; A is 3- to 12-membered heterocycle;and B is 6- to 12-membered bicyclic heterocycle. In some embodiments, His thienopyrimidinyl, optionally substituted with one or more R⁵⁰; A is3- to 12-membered heterocycle; B is 6- to 12-membered bicyclicheterocycle; m is an integer from 0 to 3; and n is an integer from 1 to3. In some embodiments, H is 9- to 10-membered bicyclic heterocycle,optionally substituted with one or more R⁵⁰; A is 5- to 7-memberedheterocycle; and B is 9-membered bicyclic heterocycle, wherein each ofsaid heterocycles comprises at least one nitrogen atom. In someembodiments, H is 9- to 10-membered bicyclic heterocycle, optionallysubstituted with one or more R⁵⁰; A is 5- to 7-membered heterocycle; Bis 9-membered bicyclic heterocycle; and n is an integer from 1 to 3,wherein each of said heterocycles comprises at least one nitrogen atom.

In some embodiments, for a compound of Formula (I), L¹ comprises lessthan 10 atoms, L² comprises less than 10 atoms, and L³ comprises lessthan 20 atoms. In some embodiments, L¹, L² and L³ each comprise at least1 atom, such as at least 2 atoms. In some embodiments, L¹, L² and L³ areeach independently selected from bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—, —S(O)—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)₂N(R⁵¹)—, alkylene, alkenylene, heteroalkylene, andheteroalkenylene. In some embodiments, L¹, L² and L³ are eachindependently selected from —CH₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —N(R⁵¹)—,—N(R⁵¹)CH₂—, —N(R⁵¹)C(O)—, and —N(R⁵¹)S(O)₂—. In some embodiments, L¹ isselected from —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—,—C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—, —S(O)—,—N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, alkylene, alkenylene,heteroalkylene, and heteroalkenylene; and L² and L³ are independentlyselected from C₁₋₄ alkylene, optionally substituted with one or moreR⁵⁰. In some embodiments, L¹, L² and L³ are each independently selectedfrom —O—, —S—, —N(R⁵¹)—; C₁₋₄ alkylene and 1- to 4-memberedheteroalkylene, each of which is optionally substituted with one or moreR⁵⁰. In some embodiments, L¹ is —NH—, L² is —CH₂—, and L³ is C₁₋₄alkylene, optionally substituted with one or more R⁵⁰.

In some embodiments, for a compound of Formula (II), L¹ comprises lessthan 10 atoms, L² comprises less than 10 atoms, and L³ comprises lessthan 20 atoms. In some embodiments, L¹, L² and L³ each comprise at least1 atom, such as at least 2 atoms. In some embodiments, L¹ and L² areeach independently selected from bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—C(O)—, —C(O)O—, —OC(O)—, —C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—, —S(O)—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)₂N(R⁵¹)—, alkylene, alkenylene, heteroalkylene, andheteroalkenylene, and L³ is selected from C₁₋₁₀ alkylene and C₂₋₁₀alkenylene, substituted with one or more R⁵⁶ and optionally furthersubstituted with one or more R⁵⁰. In some embodiments, L¹ and L² areeach independently selected from —CH₂—, —N(R⁵¹)—, —N(R⁵¹)CH₂—,—N(R⁵¹)C(O)—, and —N(R⁵¹)S(O)₂—, and L³ is selected from C₁₋₁₀ alkyleneand C₂₋₁₀ alkenylene, substituted with one or more R⁵⁶ and optionallyfurther substituted with one or more R⁵⁰. In some embodiments, L¹ isselected from —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—,—C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —S(O)₂—, —S(O)—,—N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—, alkylene, alkenylene,heteroalkylene, and heteroalkenylene; and L² is C₁₋₄ alkylene,optionally substituted with one or more R⁵⁰, and L³ is C₁₋₄ alkylenesubstituted with one or more R⁵⁶ and optionally further substituted withone or more R⁵⁰. In some embodiments, L¹ and L² are each independentlyselected from —O—, —S—, —N(R⁵¹)—; C₁₋₄ alkylene and 1- to 4-memberedheteroalkylene, each of which is optionally substituted with one or moreR⁵⁰, and L³ is C₁₋₄ alkylene substituted with one or more R⁵⁶ andoptionally further substituted with one or more R⁵⁰. In someembodiments, L¹ is —NH—, L² is —CH₂—, and L³ is C₁₋₄ alkylenesubstituted with one or more R⁵⁶ and optionally further substituted withone or more R⁵⁰.

In certain aspects, for a compound of Formula (I):

H is 5- to 12-membered heterocycle, optionally substituted with one ormore R⁵⁰;

A, B, and C are each independently selected from 3- to 12-memberedheterocycle;

L¹, L² and L³ are each independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂₀—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰, wherein two R⁵⁰ groups attached to thesame atom or different atoms of any one of L¹, L² or L³ can togetheroptionally form a ring;

R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups or two R^(C)groups attached to the same atom or different atoms can togetheroptionally form a ring;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 6;

R⁵⁰ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²);    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;        and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴; C₁₋₆        alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   —S(—50 O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —S(—50 O)R⁵², —S(═O)₂R⁵⁸,        —S(═O)₂N(R⁵²)², —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, and —P(O)(R⁵²)₂; and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle,

wherein for a compound or salt of Formula (I), when C is azetidinylene,piperidinylene or piperazinylene and R⁵⁷ is —S(—50 O)₂R⁵⁸,—S(═O)₂N(R⁵²)₂, or —NR⁵²S(═O)₂R⁵²:

p is an integer from 1 to 6; and/or

L³ is substituted with one or more R⁵⁰, wherein L³ is not —CH₂CH(OH)—.

In certain aspects, for a compound of Formula (II):

H is 5- to 12-membered heterocycle, optionally substituted with one ormore R⁵⁰;

A, B and C are each independently selected from 3- to 12-memberedheterocycle;

L¹ and L² are each independently selected from bond, —O—, —S—, —N(R⁵¹)—,—N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂₀—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰, wherein two R⁵⁰ groups attached to thesame atom or different atoms of L¹ or L² can together optionally form aring;

L³ is selected from C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene,each of which is substituted with one or more R⁵⁶ and optionally furthersubstituted with one or more R⁵⁰;

R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups or two R^(C)groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 6;

R⁵⁰ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²);

C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂,—NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵²,—C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,—NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,—C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²),C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle; and

C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,

wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle in R⁵⁰is independently optionally substituted with one or more substituentsselected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,—S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)², —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —N(R⁵²)₂,        —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)², —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,        —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂,        —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁶ is independently selected at each occurrence from:

-   -   —OR⁵⁹, ═O, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl,    -   wherein each C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl in        R⁵⁶ is independently optionally substituted at each occurrence        with one or more substituents selected from halogen, —NO₂, —CN,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂ carbocycle,        and 3- to 12-membered heterocycle;    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁶ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —N(R⁵²)₂,        —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,        —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)²,        —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂,        —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆        alkenyl, and C₂₋₆ alkynyl; and    -   further wherein R⁵⁶ optionally forms a bond to ring C; and

R⁵⁹ is independently selected at each occurrence from C₁₋₂₀ alkyl, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle,and 3- to 12-membered heterocycle, each of which is optionallysubstituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH,—OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle,

wherein for a compound or salt of Formula (II), when R⁵⁶ is —CH₃, L³ isnot further substituted with —OH, —NH₂, or —CN.

In certain aspects, for a compound of Formula (I):

H is thienopyrimidinyl, optionally substituted with one or more R⁵⁰;

A is selected from piperidinylene and piperazinylene;

B is indolylene;

L¹ and L² are each independently selected from —O—, —S—, —NH—, and—CH₂—;

L³ is selected from bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—,—C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—, —C(O)N(R⁵¹)C(O)—,—C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—,—OC(O)N(R⁵¹)—, —C(NR⁵¹)—, —N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—,—N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—, —OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—,—S(O)₂₀—, —N(R⁵¹)S(O)₂—, —S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—,—N(R⁵¹)S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene,alkynylene, heteroalkylene, heteroalkenylene, and heteroalkynylene, eachof which is optionally substituted with one or more R⁵⁰, wherein two R⁵⁰groups attached to the same atom or different atoms of L³ can togetheroptionally form a ring;

R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups or two R^(C)groups attached to the same atom or different atoms can togetheroptionally form a ring;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 6;

R⁵⁷ is selected from:

-   -   —S(—50 O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂; and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —S(—50 O)R⁵², —S(═O)₂R⁵⁸,        —S(═O)₂N(R⁵²)², —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —NR⁵²C(O)N(R⁵²)₂,        —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, and —P(O)(R⁵²)₂; and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle,

wherein for a compound or salt of Formula (I), when C is azetidinylene,piperidinylene or piperazinylene and R⁵⁷ is —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,or —NR⁵²S(═O)₂R⁵²:

p is an integer from 1 to 6; and/or

L³ is substituted with one or more R⁵⁰, wherein L³ is not —CH₂CH(OH)—.

In certain aspects, for a compound of Formula (II):

H is thienopyrimidinyl, optionally substituted with one or more R⁵⁰;

A is selected from piperidinylene and piperazinylene;

B is indolylene;

L¹ and L² are each independently selected from —O—, —S—, —NH—, and—CH₂—;

L³ is selected from C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene,each of which is substituted with one or more R⁵⁶ and optionally furthersubstituted with one or more R⁵⁰;

R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups or two R^(C)groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

m is an integer from 0 to 3;

n is an integer from 1 to 3;

p is an integer from 0 to 6;

R⁵⁶ is independently selected at each occurrence from:

-   -   —OR⁵⁹, ═O, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl,        wherein each C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl in        R⁵⁶ is independently optionally substituted at each occurrence        with one or more substituents selected from halogen, —NO₂, —CN,        —OR⁵⁹, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁶ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and    -   further wherein R⁵⁶ optionally forms a bond to ring C; and

R⁵⁹ is independently selected at each occurrence from C₁₋₂₀ alkyl, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle,and 3- to 12-membered heterocycle, each of which is optionallysubstituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH,—OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle,

wherein for a compound or salt of Formula (II), when R⁵⁶ is —CH₃, L³ isnot further substituted with —OH, —NH₂, or —CN.

In certain aspects, a compound of Formula (I) may be represented by:

such as

In some embodiments, R¹ is selected from R⁵⁰. In some embodiments, R¹ isC₁₋₃ haloalkyl, such as —CH₂CF₃. In some embodiments, R² is selectedfrom R⁵⁰. In some embodiments, R² is selected from hydrogen, halogen,—OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl. In someembodiments, R² is selected from halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂,—CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵², —CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl, such asR² is selected from —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, and C₁₋₂ alkyl.Optionally, R² is selected from —NH₂, —CH₃, —OCH₃, —CH₂OH, and —NHCH₃.In some embodiments, R³ is selected from hydrogen, halogen, —OH,—N(R⁵²)₂, —CN, —C(O)OR⁵², C₁₋₃ alkyl, and C₁₋₃ haloalkyl. In someembodiments, R⁵¹ is selected from selected from hydrogen and alkyl, suchas R⁵¹ is hydrogen. In some embodiments, R^(A) is selected from halogen,—CN, —N(R⁵²)₂, —NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —NR⁵²C(O)R⁵²,—C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, ═O, CC₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀ alkynyl. In someembodiments, m is 0. In some embodiments, L² is selected from —O—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, C₁₋₄ alkylene and C₁₋₄ heteroalkylene. In someembodiments, L² is C₁₋₄ alkylene, optionally substituted with one ormore R⁵⁰. In some embodiments, L² is C₁₋₂ alkylene, optionallysubstituted with one or more R⁵⁰. In some embodiments, L² is selectedfrom —CH₂—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —N(R⁵¹)C(O)—, and —N(R⁵¹)S(O)₂—. Insome embodiments, L² is —CH₂-. In some embodiments, R^(B) is present atone or more positions of the indole, such as at position 2, 3, 4, or 6of the indole. In some embodiments, R^(B) is selected from halogen, —CN,—N(R⁵²)₂, —NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —NR⁵²C(O)R⁵²,—C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, ═O, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀alkynyl, optionally substituted C₁₋₁₀ alkyl, optionally substitutedC₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀ alkynyl. In someembodiments, R^(B) is selected from halogen, —CN, —N(R⁵²)₂, —NR⁵³R⁵⁴,C₁₋₃ alkyl, and optionally substituted C₁₋₃ alkyl, such as R^(B) isselected from halogen, —CN, —N(R⁵²)₂, —NR⁵³R⁵⁴, and C₁₋₂ alkyl. In someembodiments, n is an integer from 1 to 4, such as an integer from 2 to3. In some embodiments, n is 2. In some embodiments, L³ is selected fromC₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene, each of which issubstituted with one or more R⁵⁰. In some embodiments, L³ is C₁₋₆alkylene, optionally substituted with one or more R⁵⁰. In someembodiments, L³ is C₂ alkylene substituted with at least one C₁₋₃ alkylor C₁₋₃ haloalkyl, and optionally further substituted with one or moreR⁵⁰. In some embodiments, L³ is substituted with ═O, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₃ alkyl(cyclopropyl), C₁₋₃ alkyl(NR⁵²C(O)R⁵²) or —O(C₁₋₆alkyl). In some embodiments, L³ is substituted with —CH₃. In someembodiments, L³ is selected from

where R⁵⁰ is optionally methyl. In some embodiments, C is 3- to12-membered heterocycle, such as 5- to 12-membered heterocycle. In someembodiments, the heterocycle is saturated. In some embodiments, C isselected from 5- to 7-membered monocyclic heterocycle, 8- to 10-memberedfused bicyclic heterocycle, and 7- to 12-membered spirocyclicheterocycle. In some embodiments, the heterocycle comprises at least onenitrogen atom, such as one or two nitrogen atoms. In some embodiments, Ccomprises at least one ring nitrogen. In some embodiments, C is selectedfrom piperidinyl and piperazinyl, such as

In some embodiments, C is selected from

In some embodiments, C is selected from In

some embodiments, C is selected from

optionally substituted with one or more R^(C). In some embodiments, C isselected from

wherein R⁵⁷ is selected from —S(—50 O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²; and C₁₋₁₀ alkyl substituted with one ormore substituents selected from —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, and —NR⁵²S(═O)₂R⁵². In some embodiments, R⁵⁷ is selectedfrom —S(—50 O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵², suchas R⁵⁷ is selected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃,and —S(—50 O)₂NHCH₃. In some embodiments, C is selected from

In some embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, and —C(O)NR⁵³R⁵⁴. Insome embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, C₁₋₆alkyl, and C₁₋₆ alkyl substituted with —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, or —C(O)NR⁵³R⁵⁴.

In some embodiments, C is selected from

In some embodiments, R^(C) is selected from —C(O)R⁵², —S(═O)R⁵²,—S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², ═O, C₁₋₃alkyl, and C₁₋₃ haloalkyl, or two R^(C) groups attached to differentatoms can together form a C₁₋₃ bridge. In some embodiments, R^(C) isselected from C₁₋₃ alkyl and C₁₋₃ haloalkyl, such as —CH₃. In someembodiments, p is selected from an integer 0 to 4, such as p is selectedfrom an integer 0 to 2. In some embodiments, p is 0. In someembodiments, R⁵⁷ is selected from —S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)NH(C₁₋₆—C(O)NR⁵³R⁵⁴; and C₁₋₆ alkyl and C₂₋₆ alkenyl, each of whichis independently substituted at each occurrence with one or moresubstituents selected from —S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selectedfrom —S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, and C₁₋₆ alkyl substituted withone or more substituents selected from —S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, and—NR⁵²S(═O)₂NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selected from —S(—50O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵². In someembodiments, R⁵⁷ is selected from —S(—50 O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂,—NHS(═O)₂CH₃, and —S(═O)₂NHCH_(3.)

In certain aspects, a compound of Formula (I) may be represented by:

such as

In some embodiments, R² is selected from R⁵⁰. In some embodiments, R² isselected from hydrogen, halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃alkenyl, and C₂₋₃ alkynyl. In some embodiments, R² is selected fromhalogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵²,—CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl,and C₂₋₃ alkynyl, such as R² is selected from —OH, —OR⁵², —NH₂,—N(R⁵²)₂, —CN, and C₁₋₂ alkyl. Optionally, R² is selected from —NH₂,—CH₃, —OCH₃, —CH₂OH, and —NHCH₃. In some embodiments, R^(B) is selectedfrom halogen, —CN, —OR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,—OC(O)R⁵², —NR⁵²C(O)R⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, ═O, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, optionally substituted C₁₋₁₀ alkyl,optionally substituted C₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀alkynyl. In some embodiments, R^(B) is selected from halogen, —CN,—OR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, C₁₋₃ alkyl, and optionally substituted C₁₋₃alkyl, such as R^(B) is selected from halogen, —CN, —OR⁵², —N(R⁵²)₂,—NR⁵³R⁵⁴, and C₁₋₂ alkyl. In some embodiments, L³ is selected from C₁₋₆alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene, each of which issubstituted with one or more R⁵⁰. In some embodiments, L³ is C₁₋₆alkylene, optionally substituted with one or more R⁵⁰. In someembodiments, L³ is C₂ alkylene substituted with at least one C₁₋₃ alkylor C₁₋₃ haloalkyl, and optionally further substituted with one or moreR⁵⁰. In some embodiments, L³ is substituted with ═O, C₁₋₆ alkyl, C₁₋₆haloalkyl, C₁₋₃ alkyl(cyclopropyl), C₁₋₃ alkyl(NR⁵²C(O)R⁵²) or —O(C₁₋₆alkyl). In some embodiments, L³ is substituted with —CH₃. In someembodiments, L³ is selected from

where R⁵⁰ is optionally methyl. In some embodiments, C is 3- to12-membered heterocycle, such as 5- to 12-membered heterocycle. In someembodiments, the heterocycle is saturated. In some embodiments, C isselected from 5- to 7-membered monocyclic heterocycle, 8- to 10-memberedfused bicyclic heterocycle, and 7- to 12-membered spirocyclicheterocycle. In some embodiments, the heterocycle comprises at least onenitrogen atom, such as one or two nitrogen atoms. In some embodiments, Ccomprises at least one ring nitrogen. In some embodiments, C is selectedfrom piperidinyl and piperazinyl, such as

In some embodiments, C is selected from

In some embodiments, C is selected from

In some embodiments, C is selected from

optionally substituted with one or more R^(C). In some embodiments, C isselected from

wherein R⁵⁷ is selected from —S(—50 O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²; and C₁₋₁₀ alkyl substituted with one ormore substituents selected from —S(—50 O)R⁵², —S(═O)₂R⁵²,—S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, and —NR⁵²S(═O)₂R⁵². In some embodiments,R⁵⁷ is selected from —S(—50 O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and—NR⁵²S(═O)₂R⁵², such as R⁵⁷ is selected from —S(—50 O)CH₃, —S(═O)₂CH₃,—S(═O)₂NH₂, —NHS(═O)₂CH₃, and —S(—50 O)₂NHCH₃. In some embodiments, C isselected from

In some embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, and —C(O)NR⁵³R⁵⁴. Insome embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, C₁₋₆alkyl, and C₁₋₆ alkyl substituted with —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, or —C(O)NR⁵³R⁵⁴. Insome embodiments, C is selected from

In some embodiments, R^(C) is selected from —C(O)R⁵², —S(═O)R⁵²,—S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², ═O, C₁₋₃alkyl, and C₁₋₃ haloalkyl, or two R^(C) groups attached to differentatoms can together form a C₁₋₃ bridge. In some embodiments, R^(C) isselected from C₁₋₃ alkyl and C₁₋₃ haloalkyl, such as —CH₃. In someembodiments, p is selected from an integer 0 to 4, such as p is selectedfrom an integer 0 to 2. In some embodiments, p is 0. In someembodiments, R⁵⁷ is selected from —S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵, —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)NH(C₁₋₆—C(O)NR⁵³R⁵⁴; and C₁₋₆ alkyl and C₂₋₆ alkenyl, each of whichis independently substituted at each occurrence with one or moresubstituents selected from —S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)NH(C₁₋₆ alkyl), —C(O)NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selectedfrom —S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)², —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, and C₁₋₆ alkyl substituted withone or more substituents selected from —S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, and—NR⁵²S(═O)₂NR⁵³R⁵⁴. In some embodiments, R⁵⁷ is selected from —S(—50O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵². In someembodiments, R⁵⁷ is selected from —S(—50 O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂,—NHS(═O)₂CH₃, and —S(═O)₂NHCH₃.

In certain aspects, a compound of Formula (I) may be represented by:

such as

In some embodiments, C is selected from 5- to 7-membered monocyclicheterocycle, such as piperidinyl and piperazinyl. In some embodiments,R⁵⁰ is selected from deuterium, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and —OR⁵²,such as R⁵⁰ is methyl. In some embodiments, R⁵⁷ is selected from —S(—50O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵², such as R⁵⁷ isselected from —S(—50 O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃, and—S(—50 O)₂NHCH₃. In some embodiments, R⁵⁷ is —S(—50 O)₂CH₃. In someembodiments, R⁵⁰ is methyl and R⁵⁷ is —S(—50 O)₂CH₃. In someembodiments, R² is selected from hydrogen, halogen, —OH, —OR⁵², —NH₂,—N(R⁵²)₂, —CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵², —CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl, such asR² is selected from —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, and C₁₋₂ alkyl. Insome embodiments, R² is methyl or —NHCH₃. In some embodiments, R² is H.

In certain aspects, a compound of Formula (I) may be represented by:

such as

In some embodiments, C is selected from 5- to 7-membered monocyclicheterocycle, such as piperidinyl and piperazinyl. In some embodiments,R⁵⁰ is selected from deuterium, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and —OR⁵²,such as R⁵⁰ is methyl. In some embodiments, R⁵⁷ is selected from —S(—50O)R⁵², —S(═O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵², such as R⁵⁷ isselected from —S(—50 O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃, and—S(—50 O)₂NHCH₃. In some embodiments, R⁵⁷ is —S(—50 O)₂CH₃. In someembodiments, R⁵⁰ is methyl and R⁵⁷ is —S(—50 O)₂CH₃. In someembodiments, R² is selected from hydrogen, halogen, —OH, —OR⁵², —NH₂,—N(R⁵²)₂, —CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵², —CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl, such asR² is selected from —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, and C₁₋₂ alkyl. Insome embodiments, R² is methyl or —NHCH₃. In some embodiments, R² is H.

In certain aspects, a compound of Formula (II) may be represented by:

In some embodiments, R¹ is selected from R⁵⁰. In some embodiments, R¹ isC₁₋₃ haloalkyl, such as —CH₂CF₃. In some embodiments, R² is selectedfrom R⁵⁰. In some embodiments, R² is selected from hydrogen, halogen,—OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl. In someembodiments, R² is selected from halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂,—CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵², —CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl, such as R² isselected from —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, and C₁₋₂ alkyl.Optionally, R² is selected from —NH₂, —CH₃, —OCH₃, —CH₂OH, and —NHCH₃.In some embodiments, R³ is selected from hydrogen, halogen, —OH,—N(R⁵²)₂, —CN, —C(O)OR⁵², C₁₋₃ alkyl, and C₁₋₃ haloalkyl. In someembodiments, R⁵¹ is selected from selected from hydrogen and alkyl, suchas R⁵¹ is hydrogen. In some embodiments, R^(A) is selected from halogen,—CN, —OR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—NR⁵²C(O)R⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, ═O, C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, C₂₋₁₀ alkynyl, optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀ alkynyl. Insome embodiments, m is 0. In some embodiments, L² is selected from —O—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, C₁₋₄ alkylene and C₁₋₄ heteroalkylene. In someembodiments, L² is C₁₋₄ alkylene, optionally substituted with one ormore R⁵⁰. In some embodiments, L² is C₁₋₂ alkylene, optionallysubstituted with one or more R⁵⁰. In some embodiments, L² is selectedfrom —CH₂—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —N(R⁵¹)C(O)—, and —N(R⁵¹)S(O)₂—. Insome embodiments, L² is —CH₂—. In some embodiments, R^(B) is present atone or more positions of the indole, such as at position 2, 3, 4, or 6of the indole. In some embodiments, R^(B) is selected from halogen, —CN,—OR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —NR⁵²C(O)R⁵²,NR⁵²C(O)R⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, ═O, C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, optionally substituted C₁₋₁₀ alkyl, optionallysubstituted C₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀ alkynyl. Insome embodiments, R^(B) is selected from halogen, —CN, —OR⁵², —N(R⁵²)₂,N(R⁵²)₂, —NR⁵³R⁵⁴, C₁₋₃ alkyl, and optionally substituted C₁₋₃ alkyl,such as R^(B) is selected from halogen, —CN, —OR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,and C₁₋₂ alkyl. In some embodiments, n is an integer from 1 to 4, suchas an integer from 2 to 3. In some embodiments, n is 2. In someembodiments, L³ is selected from alkylene, alkenylene, and alkynylene,each of which is substituted with one or more R⁵⁶ and optionally furthersubstituted with one or more R⁵⁰. In some embodiments, L³ is selectedfrom C₁₋₆ alkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene, each of whichis substituted with one or more R⁵⁶ and optionally further substitutedwith one or more R⁵⁰. In some embodiments, L³ is selected from C₁₋₆alkylene, which is substituted with one or more R⁵⁶ and optionallyfurther substituted with one or more R⁵⁰. In some embodiments, L³ is C2alkylene substituted with at least one C₁₋₃ alkyl or C₁₋₃ haloalkyl, andoptionally further substituted with one or more R⁵⁰. In someembodiments, L³ is substituted with ═O, C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₃alkyl(cyclopropyl), C₁₋₃ alkyl(NR⁵²C(O)R⁵²) or —O(C₁₋₆ alkyl). In someembodiments, L³ is substituted with —CH₃. In some embodiments, L³ isselected from

where R⁵⁶ is optionally methyl. In some embodiments, C is selected fromC₃₋₁₂ carbocycle and 3- to 12-membered heterocycle, such as 5- to12-membered heterocycle. In some embodiments, the heterocycle issaturated. In some embodiments, C is selected from 5- to 7-memberedmonocyclic heterocycle, 8- to 10-membered fused bicyclic heterocycle,and 7- to 12-membered spirocyclic heterocycle. In some embodiments, theheterocycle comprises at least one nitrogen atom, such as one or twonitrogen atoms. In some embodiments, C comprises at least one ringnitrogen. In some embodiments, C is selected from piperidinyl andpiperazinyl, such as

wherein R⁵⁷ is selected from hydrogen and R⁵⁰. In some embodiments, C isselected from

wherein R⁵⁷ is selected from hydrogen and R⁵⁰. In some embodiments, C isselected from

wherein R⁵⁷ is selected from hydrogen and R⁵⁰. In some embodiments, C isselected from

optionally substituted with one or more R^(C), wherein R⁵⁷ is selectedfrom hydrogen and R⁵⁰ In some embodiments, C is selected from

wherein R⁵⁷ is selected from —S(—50 O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²; and C₁₋₁₀ alkyl substituted with one ormore substituents selected from —S(—50 O)R⁵², —S(═O)₂R⁵²,—S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, and —NR⁵²S(═O)₂R⁵². In some embodiments,R⁵⁷ is selected from —S(—50 O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, and—NR⁵²S(═O)₂R⁵², such as R⁵⁷ is selected from —S(—50 O)CH₃, —S(═O)₂CH₃,—S(═O)₂NH₂, —NHS(═O)₂CH₃, and —S(═O)₂NHCH₃. In some embodiments, C isselected from

In some embodiments, R^(C) is selected from —C(O)R⁵², —S(═O)R⁵²,—S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², ═O, C₁₋₃alkyl, and C₁₋₃ haloalkyl, or two R^(C) groups attached to differentatoms can together form a C₁₋₃ bridge. In some embodiments, R^(C) isselected from C₁₋₃ alkyl and C₁₋₃ haloalkyl, such as —CH₃. In someembodiments, p is selected from an integer 0 to 4, such as p is selectedfrom an integer 0 to 2. In some embodiments, p is 0. In someembodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,—NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, and —C(O)NR⁵³R⁵⁴. In some embodiments,R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —C(O)R⁵²,—C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,—NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, C₁₋₆ alkyl, and C₁₋₆ alkylsubstituted with —N(R⁵²)₂, —NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —C(O)R⁵²,—C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,—NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, or —C(O)NR⁵³R⁵⁴.

In some embodiments, C is selected from

In certain aspects, a compound of Formula (II) may be represented by:

such as

In some embodiments, R² is selected from R⁵⁰. In some embodiments, R² isselected from hydrogen, halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃alkyl, C₁₋₃ alkyl-OR⁵², C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃alkenyl, and C₂₋₃ alkynyl. In some embodiments, R² is selected fromhalogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵²,—CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl,and C₂₋₃ alkynyl, such as R² is selected from —OH, —OR⁵², —NH₂,—N(R⁵²)₂, —CN, and C₁₋₂ alkyl. Optionally, R² is selected from —NH₂,—CH₃, —OCH₃, —CH₂OH, and —NHCH₃. In some embodiments, R^(B) is selectedfrom halogen, —CN, —OR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,—OC(O)R⁵², —NR⁵²C(O)R⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, ═O, C₁₋₁₀ alkyl,C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, optionally substituted C₁₋₁₀ alkyl,optionally substituted C₂₋₁₀ alkenyl, and optionally substituted C₂₋₁₀alkynyl. In some embodiments, R^(B) is selected from halogen, —CN,—OR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, C₁₋₃ alkyl, and optionally substituted C₁₋₃alkyl, such as R^(B) is selected from halogen, —CN, —OR⁵², —N(R⁵²)₂,—NR⁵³R⁵⁴, and C₁₋₂ alkyl. In some embodiments, L³ is selected fromalkylene, alkenylene, and alkynylene, each of which is substituted withone or more R⁵⁶ and optionally further substituted with one or more R⁵⁰.In some embodiments, L³ is selected from C₁₋₆ alkylene, C₂₋₆ alkenylene,and C₂₋₆ alkynylene, each of which is substituted with one or more R⁵⁶and optionally further substituted with one or more R⁵⁰. In someembodiments, L³ is selected from C₁₋₆ alkylene, which is substitutedwith one or more R⁵⁶ and optionally further substituted with one or moreR⁵⁰. In some embodiments, L³ is C₂ alkylene substituted with at leastone C₁₋₃ alkyl or C₁₋₃ haloalkyl, and optionally further substitutedwith one or more R⁵⁰. In some embodiments, L³ is substituted with ═O,C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₁₋₃ alkyl(cyclopropyl), C₁₋₃alkyl(NR⁵²C(O)R⁵²) or —O(C₁₋₆ alkyl). In some embodiments, L³ issubstituted with —CH₃. In some embodiments, L³ is selected from

where R⁵⁶ is optionally methyl. In some embodiments, C is selected fromC₃₋₁₂ carbocycle and 3- to 12-membered heterocycle, such as 5- to12-membered heterocycle. In some embodiments, the heterocycle issaturated. In some embodiments, C is selected from 5- to 7-memberedmonocyclic heterocycle, 8- to 10-membered fused bicyclic heterocycle,and 7- to 12-membered spirocyclic heterocycle. In some embodiments, theheterocycle comprises at least one nitrogen atom, such as one or twonitrogen atoms. In some embodiments, C comprises at least one ringnitrogen. In some embodiments, C is selected from piperidinyl andpiperazinyl, such as

wherein R⁵⁷ is selected from hydrogen and R⁵⁰. In some embodiments, C isselected from

wherein R⁵⁷ is selected from hydrogen and R⁵⁰. In some embodiments, C isselected from

wherein R⁵⁷ is selected from hydrogen and R⁵⁰. In some embodiments, C isselected from

optionally substituted with one or more R^(C), wherein R⁵⁷ is selectedfrom hydrogen and R⁵⁰ In some embodiments, C is selected from

wherein R⁵⁷ is selected from —S(—50 O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²; and C₁₋₁₀ alkyl substituted with one ormore substituents selected from —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, and —NR⁵²S(═O)₂R⁵². In some embodiments, R⁵⁷ is selectedfrom —S(—50 O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵², suchas R⁵⁷ is selected from —S(═O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃,and —S(—50 O)₂NHCH₃. In some embodiments, C is selected from

In some embodiments, R^(C) is selected from —C(O)R⁵², —S(═O)R⁵²,—S(═O)₂R⁵², —S(═O)₂N(R⁵²)², —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², ═O, C₁₋₃alkyl, and C₁₋₃ haloalkyl, or two R^(C) groups attached to differentatoms can together form a C₁₋₃ bridge. In some embodiments, R^(C) isselected from C₁₋₃ alkyl and C₁₋₃ haloalkyl, such as —CH₃. In someembodiments, p is selected from an integer 0 to 4, such as p is selectedfrom an integer 0 to 2. In some embodiments, p is 0. In someembodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, and —C(O)NR⁵³R⁵⁴.

In some embodiments, R^(C) is selected from —N(R⁵²)₂, —NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂,—C(O)NR⁵³R⁵⁴, C₁₋₆ alkyl, and C₁₋₆ alkyl substituted with —N(R⁵²)₂,—NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —C(O)R⁵², —C(O)OR⁵², —NR⁵²C(O)R⁵²,—NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,—C(O)N(R⁵²)₂, or —C(O)NR⁵³R⁵⁴.

In some embodiments, C is selected from

In certain aspects, a compound of Formula (II) may be represented by:

such as

In some embodiments, C is selected from 5- to 7-membered monocyclicheterocycle, such as piperidinyl and piperazinyl. In some embodiments,R⁵⁶ is selected from deuterium, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and —OR⁵⁹,such as R⁵⁶ is methyl. In some embodiments, R^(C) is selected from—S(—50 O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵², such asR^(C) is selected from —S(—50 O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂,—NHS(═O)₂CH₃, and —S(—50 O)₂NHCH₃. In some embodiments, p is an integerfrom 1 to 3, such as p is 1. In some embodiments, R^(C) is —S(—50O)₂CH₃. In some embodiments, R⁵⁶ is methyl and R^(C) is —S(—50 O)₂CH₃.In some embodiments, R² is selected from hydrogen, halogen, —OH, —OR⁵²,—NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵², —CH₂NH₂, —CH₂N(R⁵²)₂,C₁₋₃ alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl, suchas R² is selected from —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, and C₁₋₂ alkyl.In some embodiments, R² is methyl or —NHCH₃. In some embodiments, R² isH.

In certain aspects, a compound of Formula (II) may be represented by:

such as

In some embodiments, C is selected from 5- to 7-membered monocyclicheterocycle, such as piperidinyl and piperazinyl. In some embodiments,R⁵⁶ is selected from deuterium, C₁₋₄ alkyl, C₁₋₄ haloalkyl, and —OR⁵⁹,such as R⁵⁶ is methyl. In some embodiments, R^(C) is selected from—S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, and —NR⁵²S(═O)₂R⁵², such as R^(C)is selected from —S(—50 O)CH₃, —S(═O)₂CH₃, —S(═O)₂NH₂, —NHS(═O)₂CH₃, and—S(—50 O)₂NHCH₃. In some embodiments, p is an integer from 1 to 3, suchas p is 1. In some embodiments, R^(C) is —S(—50 O)₂CH₃. In someembodiments, R⁵⁶ is methyl and R^(C) is —S(—50 O)₂CH₃. In someembodiments, R² is selected from hydrogen, halogen, —OH, —OR⁵², —NH₂,—N(R⁵²)₂, —CN, C₁₋₃ alkyl, —CH₂OH, —CH₂OR⁵², —CH₂NH₂, —CH₂N(R⁵²)₂, C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl, such asR² is selected from —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, and C₁₋₂ alkyl. Insome embodiments, R² is methyl or —NHCH₃. In some embodiments, R² is H.

In certain embodiments, the present disclosure provides a stereoisomerof a compound of Formula (I) or (II). In some embodiments, thestereoisomer is in enantiomeric excess. In some embodiments, thestereoisomer is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, 99.5%, or 99.9%, enantiomeric excess. In some embodiments, thestereoisomer is provided in greater than 20%, 30%, 40%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99%, 99.5%, or 99.9%, enantiomeric excess. In some embodiments, thestereoisomer is in greater than 95% enantiomeric excess, such as greaterthan 99% enantiomeric excess.

In certain embodiments, the present disclosure provides a stereoisomerof a compound of Formula (I) or (II). In some embodiments, thestereoisomer is in diastereomeric excess. In some embodiments, thestereoisomer is provided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%,70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%,99%, 99.5%, or 99.9%, diastereomeric excess. In some embodiments, thestereoisomer is provided in greater than 20%, 30%, 40%, 50%, 55%, 60%,65%, 70%, 75%, 80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%,98%, 99%, 99.5%, or 99.9%, diastereomeric excess. In some embodiments,the stereoisomer is in greater than 95% diastereomeric excess, such asgreater than 99% diastereomeric excess.

In certain embodiments, the compound of Formula (I) or (II) ispreferably used as a non-racemic mixture, wherein one enantiomer ispresent in excess of its corresponding enantiomer. Typically, suchmixture will contain a mixture of the two isomers in a ratio of at leastabout 9:1, preferably at least 19:1. In some embodiments, the compoundis provided in at least 96% enantiomeric excess, meaning the compoundhas less than 2% of the corresponding enantiomer. In some embodiments,the compound is provided in at least 96% diastereomeric excess, meaningthe compound has less than 2% of the corresponding diastereomer.

In certain embodiments, the compound of Formula (I) or (II) ispreferably used as a non-racemic mixture wherein the (+)-isomer is themajor component of the mixture. Typically, such mixture will contain nomore than about 10% of the (−)-isomer, meaning the ratio of (+)- to(−)-isomers is at least about 9:1, and preferably less than 5% of the(−)-isomer, meaning the ratio of (+)- to (−)-isomers is at least about19:1. In some embodiments, the compound used has less than 2% of the(−)-isomer, meaning it has an enantiomeric excess of at least about 96%.In some embodiments, the compound has an enantiomeric excess of at least98%. In some embodiments, the compound has an enantiomeric excess of atleast 99%.

In certain embodiments, the compound of Formula (I) or (II) ispreferably used as a non-racemic mixture wherein the (−)-isomer is themajor component of the mixture. Typically, such mixture will contain nomore than about 10% of the (+)-isomer, meaning the ratio of (−)- to(+)-isomers is at least about 9:1, and preferably less than 5% of the(+)-isomer, meaning the ratio of (−)- to (+)-isomers is at least about19:1. In some embodiments, the compound used has less than 2% of the(+)-isomer, meaning it has an enantiomeric excess of at least about 96%.In some embodiments, the compound has an enantiomeric excess of at least98%. In some embodiments, the compound has an enantiomeric excess of atleast 99%.

In certain aspects, the present disclosure provides a stereoisomer of acompound of Formula (I):

or a pharmaceutically acceptable salt, isotopic form, or prodrugthereof, wherein:

H is selected from C₅₋₁₂ carbocycle and 5- to 12-membered heterocycle,each of which is optionally substituted with one or more R⁵⁰;

A is selected from bond, C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle;

B is selected from C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle;

C is 3- to 12-membered heterocycle;

L¹, L² and L³ are each independently selected from bond, —O—, —S—,—N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂₀—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰, wherein two R⁵⁰ groups attached to thesame atom or different atoms of any one of L¹, L² or L³ can togetheroptionally form a bridge or ring;

R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups or two R^(C)groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

m, n and p are each independently an integer from 0 to 6;

R⁵⁰ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²);

C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂,—NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵²,—C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,—NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,—C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²),C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle; and

-   -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)²,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵¹ is independently selected at each occurrence from:

-   -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁷ is selected from:

-   -   halogen, —NO₂, —CN, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵⁸,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)OR⁵², —OC(O)R⁵²,        —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)NH(C₁₋₆ alkyl),        —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═S, ═N(R⁵²); and    -   C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is        independently substituted at each occurrence with one or more        substituents selected from —NO₂, —CN, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,        —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,        —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,        —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,        —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)²,        —NR⁵²C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═S, and ═N(R⁵²);        and

R⁵⁸ is selected from hydrogen; and C₁₋₂₀ alkyl, C₃₋₂₀ alkenyl, C₂₋₂₀alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle.

In some embodiments, the stereoisomer of a compound of Formula (I) isprovided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or99.9%, enantiomeric excess. In some embodiments, the stereoisomer isprovided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%,or 99.9%, enantiomeric excess. In some embodiments, the stereoisomer isin greater than 95% enantiomeric excess, such as greater than 99%enantiomeric excess.

In some embodiments, for a stereoisomer of a compound of Formula (I), L³is selected from

Optionally, R⁵⁰ is methyl. In some embodiments, L³ is

In some embodiments, L³ is

In some embodiments, C is selected from

In some embodiments, L³ is selected from

and C is selected from

Any combination of the groups described above for the various variablesof a compound of Formula (I) is contemplated herein for the stereoisomerof a compound of Formula (I).

In certain aspects, the present disclosure provides a stereoisomer of acompound of Formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

H is selected from C₅₋₁₂ carbocycle and 5- to 12-membered heterocycle,each of which is optionally substituted with one or more R⁵⁰;

A, B and C are each independently selected from C₃₋₁₂ carbocycle and 3-to 12-membered heterocycle;

L¹ and L² are each independently selected from bond, —O—, —S—, —N(R⁵¹)—,—N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—, —OC(O)O—, —C(O)N(R⁵¹)—,—C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)—,—N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—, —C(NR⁵¹)—,—N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—, —S(O)₂—,—OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂₀—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—; alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰, wherein two R⁵⁰ groups attached to thesame atom or different atoms of L¹ or L² can together optionally form aring;

L³ is selected from alkylene, alkenylene, and alkynylene, each of whichis substituted with one or more R⁵⁶ and optionally further substitutedwith one or more R⁵⁰;

R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups or two R^(C)groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring;

m, n and p are each independently an integer from 0 to 6;

R⁵⁰ is independently selected at each occurrence from:

-   -   halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,        —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²);

C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂,—NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵²,—C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,—NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,—C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²),C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle; and

-   -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵⁰ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; R⁵¹ is independently        selected at each occurrence from:    -   hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; and    -   C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle,    -   wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle        in R⁵¹ is independently optionally substituted with one or more        substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,        —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆        haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl;

R⁵² is independently selected at each occurrence from hydrogen; andC₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl,C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle;

R⁵³ and R⁵⁴ are taken together with the nitrogen atom to which they areattached to form a heterocycle, optionally substituted with one or moreR⁵⁰;

R⁵⁶ is independently selected at each occurrence from:

-   -   —NO₂, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,        —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,        —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,        —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,        —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,        —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₁₀ alkyl, C₂₋₁₀        alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle and 3- to 12-membered        heterocycle,    -   wherein each C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl in        R⁵⁶ is independently optionally substituted at each occurrence        with one or more substituents selected from halogen, —NO₂, —CN,        —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,        —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,        —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵²,        —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,        —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴,        —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S,        ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle;

wherein each C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle in R⁵⁶is independently optionally substituted with one or more substituentsselected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,—S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl,C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and

-   -   further wherein R⁵⁶ optionally forms a bond to ring C; and

R⁵⁹ is independently selected at each occurrence from C₁₋₂₀ alkyl, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl, 1- to 6-membered heteroalkyl, C₃₋₁₂ carbocycle,and 3- to 12-membered heterocycle, each of which is optionallysubstituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH,—OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle.

In some embodiments, the stereoisomer of a compound of Formula (II) isprovided in at least 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, or99.9%, enantiomeric excess. In some embodiments, the stereoisomer isprovided in greater than 20%, 30%, 40%, 50%, 55%, 60%, 65%, 70%, 75%,80%, 85%, 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%,or 99.9%, enantiomeric excess. In some embodiments, the stereoisomer isin greater than 95% enantiomeric excess, such as greater than 99%enantiomeric excess.

In some embodiments, for a stereoisomer of a compound of Formula (II),L³ is selected from

Optionally, R⁵⁶ is methyl. In some embodiments, L³ is

In some embodiments, L³ is

In some embodiments, C is selected from

In some embodiments, L³ is selected from

and C is selected from

Any combination of the groups described above for the various variablesof a compound of Formula (II) is contemplated herein for thestereoisomer of a compound of Formula (II).

In certain aspects, a compound of the disclosure covalently binds tomenin and inhibits the interaction of menin with MLL. Such bonding maylead to an increase in the affinity of the compound for menin, which isan advantageous property in many applications, including therapeutic anddiagnostic uses. In some embodiments, the compounds of the disclosurecomprise electrophilic groups capable of reacting with a nucleophilicgroup present in a menin protein. Suitable electrophilic groups aredescribed throughout the application, while suitable nucleophilic groupsinclude, for example, cysteine moieties present in the binding domain ofa menin protein. Without wishing to be bound by theory, a cysteineresidue in the menin binding domain may react with the electrophilicgroup of a compound of the disclosure, leading to formation of aconjugate product. In some embodiments, the compounds of the disclosureare capable of covalently bonding to the cysteine residue at position329 of a menin isoform 2 (SEQ ID NO: 2) or cysteine 334 in menin isoform1 (SEQ ID NO: 1). In some embodiments, the disclosure provides aconjugate of a compound of the disclosure with a menin protein. Forexample, the disclosure provides a conjugate of a compound of thedisclosure with menin, bound at the cysteine residue 329 of meninisoform 2 (SEQ ID NO: 2) or cysteine 334 in menin isoform 1 (SEQ ID NO:1).

In some embodiments, for a compound of Formula (I) or (II), one or moreof R^(A), R^(B) and R^(C), when present, comprises a functional groupthat covalently reacts with one or more residues on menin. In someembodiments, the functional group covalently reacts with one or morecysteine residues on menin. In some embodiments, the functional groupcovalently reacts with a cysteine on menin at position 329 relative toSEQ ID NO: 2 when optimally aligned or position 334 relative to SEQ IDNO: 1 when optimally aligned. In some embodiments, the functional groupcovalently reacts with one or more residues on menin selected fromcysteine 329, cysteine 241, and/or cysteine 230 on menin relative to SEQID NO: 2 when optimally aligned. In some embodiments, the functionalgroup covalently reacts with cysteine 329 relative to SEQ ID NO: 2 whenoptimally aligned.

In some embodiments, for a compound of Formula (I) or (II), one or moreof R^(A), R^(B) and R^(C), when present, comprises a moiety thatcovalently reacts with one or more residues on menin. In someembodiments, one or more of R^(A), R^(B) and R^(C), when present,comprises a moiety that covalently reacts with one or more isoforms ofmenin, for example, isoform 1 (SEQ ID NO: 1), isoform 2 (SEQ ID NO: 2)or isoform 3 (SEQ ID NO: 3) of menin. In certain embodiments, one ormore of R^(A), R^(B) and R^(C), _(w)hen present, comprises a moiety thatcovalently reacts with menin, wherein the menin protein shares 60% ormore, 70% or more, 75% or more, 80% or more, 85% or more, 90% or more,95% or more, or 99% or more sequence identity with isoform 1 (SEQ ID NO:1), isoform 2 (SEQ ID NO: 2) or isoform 3 (SEQ ID NO: 3).

In some embodiments, for a compound of Formula (I) or (II), one or moreof R^(A), R^(B) and R^(C), when present, comprises an electrophilicgroup that is susceptible to nuclephilic attack from a residue on menin.Any suitable electrophilic moiety known to one of skill in the art tobind to nuclephilic residues, for example, any electrophilic moietyknown to bind to cysteine residues, is contemplated herein. In someembodiments, one or more of R^(A), R^(B) and R^(C), when present,comprises a moiety other than an electrophile, wherein the moiety iscapable of binding to or covalently reacting with a residue on menin. Insome embodiments, a compound or salt of Formula (I) or (II) is capableof (a) binding covalently to menin and (b) inhibiting the interation ofmenin and MLL.

In some embodiments, for a compound of Formula (I) or (II), R^(C)comprises a functional group that covalently reacts with one or moreresidues on menin. In some embodiments, the functional group covalentlyreacts with one or more cysteine residues on menin. In some embodiments,the functional group covalently reacts with a cysteine on menin atposition 329 relative to SEQ ID NO: 2 when optimally aligned or position334 relative to SEQ ID NO: 1 when optimally aligned.

In some embodiments, for a compound of Formula (I) or (II), R^(C) is amoiety comprising an alpha, beta-unsaturated carbonyl; an alpha,beta-unsaturated sulfonyl; an epoxide; an aldehyde; sulfonyl fluoride; ahalomethylcarbonyl, a dihalomethylcarbonyl, or a trihalomethylcarbonyl.

In some embodiments, for a compound of Formula (I) or (II), R^(C) isselected from:

-   -   wherein:    -   L⁵ is selected from a bond; and C₁₋₆ alkylene, C₁₋₆        heteroalkylene, C₂₋₆ alkenylene, and C₂₋₆ alkynylene, each of        which is independently optionally substituted with one or more        R³²;    -   R²² and R²³ are each independently selected from:        -   hydrogen, halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰,            —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰,            —S(O)₂N(R²⁰)₂, —) N(R²⁰S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰),            —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, and —CN;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰,            —S(O)₂N(R²⁰)₂,—N(R²⁰S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰),            —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₃₋₁₀            carbocycle, and 3- to 10-membered heterocycle; and        -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle,        -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered            heterocycle of R²² and R²³ is independently optionally            substituted with one or more substituents selected from            halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰,            —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰,            —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰),            —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆ alkyl,            C₂₋₆ alkenyl, and C₂₋₆ alkynyl; or R²² and R²³, together            with the carbon atoms to which they are attached, form a            carbocyclic ring;    -   R²⁴ is selected from:        -   hydrogen, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰,            —S(O)₂R²⁰, and —S(O)₂N(R²⁰)₂;        -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is            independently optionally substituted at each occurrence with            one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₃₋₁₀ carbocycle, and 3- to            10-membered heterocycle; and        -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle,        -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered            heterocycle of R²⁴ is independently optionally substituted            with one or more substituents selected from halogen, —OR²⁰,            —SR²⁰, —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰,            —C(O)N(R²⁰)₂, —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂,            —N(R²⁰S(O)₂R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,            —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, OP(O)(OR²⁰)₂, —CN, C₁₋₆ alkyl,            C₂₋₆ alkenyl, and C₂₋₆ alkynyl;    -   R²⁰ is independently selected at each occurrence from R⁵²; and    -   R³² is independently selected at each occurrence from R⁵⁰.

In some embodiments, L⁵ is a bond. In some embodiments, L⁵ is optionallysubstituted C₁₋₆ alkylene. In some embodiments, L⁵ is selected frommethylene, ethylene or propylene. In some embodiments, L⁵ is substitutedwith one or more substituents selected from halogen, —NO₂, ═O, ═S,—OR²⁰, —SR²⁰, and —N(R²⁰)₂.

In some embodiments, R²³ is selected from:

-   -   hydrogen;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —OR²⁰, —SR²⁰,        —N(R²⁰)₂, —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂,        —OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂, N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂,        ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂)₂,        —OP(O)(OR²⁰)₂, —CN, C₃₋₁₀ carbocycle and 3- to 10-membered        heterocycle; and    -   C₃₋₁₀ carbocycle, and 3- to 10-membered heterocycle,    -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle        is independently optionally substituted with one or more        substituents selected from halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂,        —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰,        —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S,        ═N(R²⁰), —P(O)(OR²⁰)₂, —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂,        —CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R²³ is selected from:

-   -   hydrogen;    -   C₁₋₆ alkyl optionally substituted with one or more substituents        selected from halogen, —OR²⁰, —SR²⁰, —N(R²⁰)², ═O, ═S, ═N(R²⁰),        and —CN; and    -   3- to 10-membered heterocycle optionally substituted with one or        more substituents selected from halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂,        —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰)₂, —OC(O)R²⁰,        —S(O)₂R²⁰, —S(O)₂N(R²⁰)₂, —N(R²⁰)S(O)₂R²⁰, —NO₂, ═O, ═S,        ═N(R²⁰), —P(O)(OR²⁰)₂, —P(O)(R₂₀)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆        alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.)

In some embodiments, R²³ is selected from hydrogen and C₁₋₆ alkyloptionally substituted with one or more substituents selected fromhalogen, —OR²⁰, —SR²⁰, —N(R²⁰)², ═O, ═S, ═N(R²⁰), and —CN.

In some embodiments, R²² is selected from:

-   -   hydrogen and —CN;    -   C₁₋₆ alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is        independently optionally substituted at each occurrence with one        or more substituents selected from halogen, —OR²⁰, —SR²⁰,        —NR²⁰)₂, —N(R²⁰)C(O)R²⁰—C(O)R²⁰, —C(O)^(0R20,) _(-C)(₀)_(N)(_(R)        ²⁰)₂, —OC(O)R²⁰, OC(O)R²⁰, —S(O)₂R²⁰, —S(O)₂N(R²⁰)²,        —N(R²⁰)S(O)²R²⁰, —NO₂, ═O, ═S, ═N(R²⁰), —P(O)(OR²⁰)₂,        —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₃₋₁₀ carbocycle and 3- to        10-membered heterocycle; and    -   C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle,    -   wherein each C₃₋₁₀ carbocycle and 3- to 10-membered heterocycle        is independently optionally substituted with one or more        substituents selected from halogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂,        —N(R²⁰)C(O)R²⁰, —C(O)R²⁰, —C(O)OR²⁰, —C(O)N(R²⁰), —OC(O)R²⁰,        S(O)₂R²⁰, —S(O)₂N(R²⁰)₂, —N(R^(20)S(O)) ₂R²⁰, —NO₂, ═O, ═S,        ═N(R²⁰), —P(O)(OR²⁰)₂, —P(O)(R²⁰)₂, —OP(O)(OR²⁰)₂, —CN, C₁₋₆        alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl.

In some embodiments, R²² is selected from hydrogen, —CN; and C₁₋₆ alkyloptionally substituted with one or more substituents selected fromhalogen, —OR²⁰, —SR²⁰, and —N(R²⁰)₂.

In some embodiments, R²² and R²³, together with the carbon atoms towhich they are attached, form a 5-, 6-, or 7-membered carbocyclic ring.

In some embodiments, R²⁴ is selected from hydrogen and C₁₋₆ alkyloptionally substituted with one or more substituents selected fromhalogen, —OR²⁰, —SR²⁰, —N(R²⁰)₂, —NO₂, ═O, and —CN.

In some embodiments, R²¹ is selected from

Any combination of the groups described above for the various variablesis contemplated herein. Throughout the specification, groups andsubstituents thereof can be chosen to provide stable moieties andcompounds.

The chemical entities described herein can be synthesized according toone or more illustrative schemes herein and/or techniques known in theart. Materials used herein are either commercially available or preparedby synthetic methods generally known in the art. These schemes are notlimited to the compounds listed in the examples or by any particularsubstituents, which are employed for illustrative purposes. Althoughvarious steps are described and depicted in Scheme 1 and Examples 1-5,the steps in some cases may be performed in a different order than theorder shown in Scheme 1 and Examples 1-5. Various modifications to thesesynthetic reaction schemes may be made and will be suggested to oneskilled in the art having referred to the disclosure contained in thisApplication. Numberings or R groups in each scheme do not necessarilycorrespond to that of the claims or other schemes or tables herein.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure, generally within a temperature range from−10° C. to 200° C. Further, except as otherwise specified, reactiontimes and conditions are intended to be approximate, e.g., taking placeat about atmospheric pressure within a temperature range of about −10°C. to about 110° C. over a period of about 1 to about 24 hours;reactions left to run overnight average a period of about 16 hours.

In general, compounds of the disclosure may be prepared by the followingreaction scheme:

In some embodiments, a compound of Formula 1-7 may be prepared accordingto Scheme 1. For example, methanesulfonyl chloride can be added to asolution of alcohol 1-1 and triethylamine to afford mesylate 1-2.Addition of mesylate 1-2 to a solution of Cs₂CO₃ and amine 1-3 canprovide a compound of Formula 1-4. Coupling of aldehyde 1-4 to amine 1-5can proceed in the presence of a suitable reducing agent, such asNaBH(OAc)₃, to give a compound of Formula 1-6. Addition of TFA canreveal the free amine, which can optionally be reacted with R⁵⁷-LG,wherein LG is a suitable leaving group, to afford a compound of Formula1-7.

In some embodiments, a compound of the present disclosure, for example,a compound of a formula given in Table 1 or 2, is synthesized accordingto one of the general routes outlined in Scheme 1, Examples 1-5, or bymethods generally known in the art. In some embodiments, exemplarycompounds may include, but are not limited to, a compound or saltthereof selected from Table 1.

TABLE 1 No. Structure MW (calc'd) m/z found 1

687.78 688.45 [M + H]⁺ 2

688.83 689.40 [M + H]⁺ 3

687.84 688.45 [M + H]⁺ 4

702.86 703.55 [M + H]⁺ 5

652.78 653.55 [M + H]⁺ 6

638.75 639.50 [M + H]⁺ 7

689.82 690.50 [M + H]⁺ 8

703.84 704.55 [M + H]⁺ 9

688.83 689.45 [M + H]⁺ 10

688.83 689.40 [M + H]⁺ 11

702.86 703.55 [M + H]⁺ 12

716.88 717.55 [M + H]⁺ 13

702.86 703.55 [M + H]⁺ 14

702.86 703.55 [M + H]⁺ 15

702.86 703.50 [M + H]⁺ 16

702.86 703.60 [M + H]⁺ 17

702.86 703.35 [M + H]⁺ 18

702.86 703.35 [M + H]⁺ 19

702.86 703.35 [M + H]⁺ 20

702.86 703.35 [M + H]⁺ 21

716.88 717.35 [M + H]⁺ 22

716.88 717.35 [M + H]⁺ 23

714.87 715.25 [M + H]⁺ 24

716.88 717.45 [M + H]⁺ 25

716.88 717.40 [M + H]⁺ 26

716.88 717.40 [M + H]⁺ 27

28

714.87 715.35 [M + H]⁺ 29

716.88 717.40 [M + H]⁺ 30

700.84 701.35 [M + H]⁺ 31

32

33

34

35

688.79 689.15 [M + H]⁺ 36

37

38

39

40

41

42

43

688.83 689.45 [M + H]⁺ 44

702.86 703.45 [M + H]⁺ 45

688.83 689.40 [M + H]⁺ 46

702.86 703.45 [M + H]⁺ 47

702.86 703.50 [M + H]⁺ 48

702.86 703.55 [M + H]⁺ 49

702.86 703.55 [M + H]⁺ 50

51

52

728.89 729.55 [M + H]⁺ 53

714.87 715.30 [M + H]⁺ 54

714.87 715.30 [M + H]⁺ 55

700.84 701.30 [M + H]⁺ 56

714.87 715.35 [M + H]⁺ 57

686.81 687.25 [M + H]⁺ 58

700.84 701.35 [M + H]⁺ 59

687.84 688.45 [M + H]⁺ 60

687.84 688.50 [M + H]⁺ 61

700.84 701.30 [M + H]⁺ 62

63

64

703.84 704.25 [M + H]⁺ 65

638.75 639.20 [M + H]⁺ 66

703.84 704.25 [M + H]⁺ 67

638.75 639.25 [M + H]⁺ 68

667.79 668.35 [M + H]⁺ 69

720.27 721.3 70

706.25 707.3 71

706.25 707.2 72

668.29 689.2 73

729.88 730.30 [M + H]⁺ 74

75

76

77

78

79

80

81

82

83

84

85

86

87

717.29 718.35 [M + H]⁺ 88

89

717.29 718.25 [M + H]⁺ 90

91

92

93

672.26 673.2667 94

714.27 715.2 [M + H]⁺ 95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

714.27 715.45 [M + H]⁺ 116

730.31 731.50 [M + H]⁺ 117

678.31 679.50 [M + H]⁺ 118

706.26 707.40 [M + H]⁺ 119

717.29 718.25 [M + H]⁺ 120

745.32 746.30 [M + H]⁺ 121

729.29 730.45 [M + H]⁺ 122

720.28 721.40 [M + H]⁺ 123

747.30 748.45 [M + H]⁺ 124

734.28 735.2 [M + H]⁺ 125

753.27 754.45 [M + H]⁺ 126

756.25 757.35 [M + H]⁺ 127

728.29 729.45 [M + H]⁺ 128

702.27 703.35 [M + H]⁺ 129

735.28 736.40 [M + H]⁺ 130

771.26 772.40 [M + H]⁺ 131

733.28 734.45 [M + H]⁺ 132

718.28 719.45 [M + H]⁺ 133

682.30 683.50 [M + H]⁺ 134

653.29 654.40 [M + H]⁺ 135

703.27 704.40 [M + H]⁺ 136

652.29 653.45 [M + H]⁺ 137

720.27 721.45 [M + H]⁺ 138

702.27 703.50 [M + H]⁺ 139

717.29 718.50 [M + H]⁺ 140

715.27 716.40 [M + H]⁺ 141

731.30 732.45 [M + H]⁺ 142

745.32 746.40 [M + H]⁺ 143

679.30 680.50 [M + H]⁺ 144

724.24 725.40 [M + H]⁺ 145

720.27 721.45 [M + H]⁺ 146

728.29 729.45 [M + H]⁺ 147

729.29 730.40 [M + H]⁺ 148

610.28 611.3 [M + H]⁺ 149

721.26 722.45 [M + H]⁺ 150

686.29 687.3 [M + H]⁺ 151

717.29 718.55 [M + H]⁺ 152

734.28 735.40 [M + H]⁺ 153

696.31 154

667.30 668.35 [M + H]⁺ 155

702.28 703.35 [M + H]⁺ 156

681.32 682.45 [M + H]⁺ 157

700.30 701.40 [M + H]⁺ 158

702.27 703.40 [M + H]⁺ 159

640.26 641.40 [M + H]⁺ 160

690.24 691.35 [M + H]⁺ 161

696.31 697.3 [M + H]⁺ 162

659.23 660.2 [M + H]⁺ 163

731.26 732.40 [M + H]⁺ 164

731.26 732.35 [M + H]⁺ 165

701.28 702.40 [M + H]⁺ 166

667.34 668.45 [M + H]⁺ 167

703.27 704.40 [M + H]⁺ 168

660.28 661.40 [M + H]⁺ 169

674.24 170

731.30 732.40 [M + H]⁺ 171

716.29 717.45 [M + H]⁺ 172

705.25 706.45 [M + H]⁺ 173

728.29 729.45 [M + H]⁺ 174

731.30 732.45 [M + H]⁺ 175

682.31 683.45 [M + H]⁺ 176

696.33 697.60 [M + H]⁺ 177

720.26 721.50 [M + H]⁺ 178

681.32 682.45 [M + H]⁺ 179

731.30 732.50 [M + H]⁺ 180

731.30 732.50 [M + H]⁺ 181

710.35 711.50 [M + H]⁺ 182

696.33 697.60 [M + H]⁺ 183

718.27 719.45 [M + H]⁺ 184

717.29 718.45 [M + H]⁺ 185

731.30 732.45 [M + H]⁺ 186

716.29 717.45 [M + H]⁺ 187

733.28 734.45 [M + H]⁺ 188

626.28 627.40 [M + H]⁺ 189

710.35 711.45 [M + H]⁺ 190

665.32 666.45 [M + H]⁺ 191

724.36 725.45 [M + H]⁺ 192

732.30 733.45 [M + H]⁺ 193

716.29 717.45 [M + H]⁺ 194

719.26 720.55 [M + H]⁺ 195

674.29 675.50 [M + H]⁺ 196

788.32 789.45 [M + H]⁺ 197

774.31 775.3 [M + H]⁺ 198

735.28 736.45 [M + H]⁺ 199

677.32 678.55 [M + H]⁺ 200

760.28 761.40 [M + H]⁺ 201

702.27 703.45 [M + H]⁺ 202

723.37 724.55 [M + H]⁺ 203

688.26 689.40 [M + H]⁺ 204

695.33 696.60 [M + H]⁺ 205

733.28 734.55 [M + H]⁺ 206

709.35 710.55 [M + H]⁺ 207

668.32 669.55 [M + H]⁺ 208

717.29 718.40 [M + H]⁺ 209

742.28 743.40 [M + H]⁺ 210

731.30 732.40 [M + H]⁺ 211

743.30 744.40 [M + H]⁺ 212

707.33 708.45 [M + H]⁺ 213

709.35 710.50 [M + H]⁺ 214

732.29 733.40 [M + H]⁺ 215

711.33 712.45 [M + H]⁺ 216

683.30 684.45 [M + H]⁺ 217

697.31 698.3 [M + H]⁺ 218

219

673.25 674.2 [M + H]⁺ 220

694.34 695.50 [M + H]⁺ 221

708.35 709.50 [M + H]⁺ 222

706.25 707.2561 225

226

228

229

648.26 230

621.26 622.2 [M + H]⁺ 231

232

233

234

235

688.26 689.40 [M + H]⁺ 236

237

238

239

717.27 718.45 [M + H]⁺ 240

793.32 794.3244 241

720.27 721.35 242

716.29 717.3 [M + H]⁺ 243

667.30 668.45 [M + H]⁺ 244

653.29 654.45 [M + H]⁺ 245

760.28 761.2872 246

718.27 719.2776 247

716.29 717.56 [M + H]⁺ 248

759.33 760.50 [M + H]⁺ 249

731.30 732.45 [M + H]⁺ 250

251

745.32 746.3 [M + H]⁺ 252

731.30 732.3 [M + H]⁺ 253

254

255

256

257

258

259

260

261

262

263

264

265

266

267

268

269

270

271

272

273

274

275

276

277

278

279

280

717.27 718.2 [M + H]⁺ 281

635.27 636.27 [M + H]⁺ 282

743.30 744.31 [M + H]⁺ 283

728.29 729.30 [M + H]⁺ 284

285

286

287

288

In some embodiments, exemplary compounds may include, but are notlimited to, a compound or salt thereof selected from Table 2.

TABLE 2 No. Structure MW (calc'd) m/z (found) 1000

1001

1002

1003

1004

1005

1006

1007

1008

1009

1010

1011

1012

1013

1014

1015

1016

673.26 337.6 [M + 2H]²⁺ 1017

1018

1019

1020

1021

1022

1023

1024

1025

1026

1027

Pharmaceutical Compositions

The compositions and methods of the present disclosure may be utilizedto treat an individual in need thereof In certain embodiments, theindividual is a mammal such as a human, or a non-human mammal. Whenadministered to an animal, such as a human, the composition or thecompound is preferably administered as a pharmaceutical compositioncomprising, for example, a compound or salt of Formula (I) or (II) and apharmaceutically acceptable carrier.

In some embodiments, the pharmaceutical composition is formulated fororal administration. In other embodiments, the pharmaceuticalcomposition is formulated for injection. In still more embodiments, thepharmaceutical compositions comprise a compound as disclosed herein andan additional therapeutic agent (e.g., anticancer agent). Non-limitingexamples of such therapeutic agents are described herein below.

Suitable routes of administration include, but are not limited to, oral,intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary,transmucosal, transdermal, vaginal, otic, nasal, and topicaladministration. In addition, by way of example only, parenteral deliveryincludes intramuscular, subcutaneous, intravenous, intramedullaryinjections, as well as intrathecal, direct intraventricular,intraperitoneal, intralymphatic, and intranasal injections.

In certain embodiments, a composition of a compound or salt of Formula(I) or (II) is administered in a local rather than systemic manner, forexample, via injection of the compound directly into an organ, often ina depot preparation or sustained release formulation. In specificembodiments, long acting formulations are administered by implantation(for example subcutaneously or intramuscularly) or by intramuscularinjection. Furthermore, in other embodiments, a compound or salt ofFormula (I) or (II) is delivered in a targeted drug delivery system, forexample, in a liposome coated with organ-specific antibody. In suchembodiments, the liposomes are targeted to and taken up selectively bythe organ. In yet other embodiments, the composition is provided in theform of a rapid release formulation, in the form of an extended releaseformulation, or in the form of an intermediate release formulation. Inyet other embodiments, the composition is administered topically.

The compound of Formula (I) or (II), or a pharmaceutically acceptablesalt thereof, may be effective over a wide dosage range. For example, inthe treatment of adult humans, dosages from 0.01 to 1000 mg per day,from 0.5 to 100 mg per day, from 1 to 50 mg per day, and from 5 to 40 mgper day are examples of dosages that may be used in some embodiments.The exact dosage will depend upon the route of administration, the formin which the compound is administered, the subject to be treated, thebody weight of the subject to be treated, and the preference andexperience of the attending physician.

In some embodiments, a compound or salt of Formula (I) or (II) isadministered in a single dose. Typically, such administration will be byinjection, e.g., intravenous injection, in order to introduce the agentquickly. However, other routes are used as appropriate. In someembodiments, a single dose of a compound or salt of Formula (I) or (II)is used for treatment of an acute condition.

In some embodiments, a compound or salt of Formula (I) or (II) isadministered in multiple doses. In some embodiments, dosing is aboutonce, twice, three times, four times, five times, six times, or morethan six times per day. In other embodiments, dosing is about once amonth, once every two weeks, once a week, or once every other day. Inanother embodiment, a compound or salt of Formula (I) or (II) andanother agent are administered together about once per day to about 6times per day. In another embodiment, the administration of a compoundor salt of Formula (I) or (II) and an agent continues for less thanabout 7 days. In yet another embodiment, the administration continuesfor more than about 6 days, more than about 10 days, more than about 14days, more than about 28 days, more than about two months, more thanabout six months, or one year or more. In some cases, continuous dosingis achieved and maintained as long as necessary.

Administration of a compound or salt of Formula (I) or (II) may continueas long as necessary. In some embodiments, a compound of the disclosureis administered for more than 1, more than 2, more than 3, more than 4,more than 5, more than 6, more than 7, more than 14, or more than 28days. In some embodiments, a compound of the disclosure is administered28 days or less, 14 days or less, 7 days or less, 6 days or less, 5 daysor less, 4 days or less, 3 days or less, 2 days or less, or 1 day or apart thereof. In some embodiments, a compound or salt of Formula (I) or(II) is administered chronically on an ongoing basis, e.g., for thetreatment of chronic effects.

In some embodiments, a compound or salt of Formula (I) or (II) isadministered in dosages. It is known in the art that due to intersubjectvariability in compound pharmacokinetics, individualization of dosingregimen is necessary for optimal therapy. Dosing for a compound or saltof Formula (I) or (II) may be found by routine experimentation in lightof the instant disclosure.

In some embodiments, a compound or salt of Formula (I) or (II) isformulated into pharmaceutical compositions. In specific embodiments,pharmaceutical compositions are formulated in a conventional mannerusing one or more physiologically acceptable carriers comprisingexcipients and auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically. Properformulation is dependent upon the route of administration chosen. Anypharmaceutically acceptable techniques, carriers, and excipients areused as suitable to formulate the pharmaceutical compositions describedherein: Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms,Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms andDrug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins1999).

Provided herein are pharmaceutical compositions comprising a compound orsalt of Formula (I) or (II) and a pharmaceutically acceptablediluent(s), excipient(s), or carrier(s). In certain embodiments, thecompounds or salts described are administered as pharmaceuticalcompositions in which a compound or salt of Formula (I) or (II) is mixedwith other active ingredients, as in combination therapy. Encompassedherein are all combinations of active ingredients set forth in thecombination therapies section below and throughout this disclosure. Inspecific embodiments, the pharmaceutical compositions include one ormore compounds of Formula (I) or (II), or a pharmaceutically acceptablesalt thereof.

A pharmaceutical composition, as used herein, refers to a mixture of acompound or salt of Formula (I) or (II) with other chemical components,such as carriers, stabilizers, diluents, dispersing agents, suspendingagents, thickening agents, and/or excipients. In certain embodiments,the pharmaceutical composition facilitates administration of thecompound to an organism. In some embodiments, practicing the methods oftreatment or use provided herein, therapeutically effective amounts of acompound or salt of Formula (I) or (II) are administered in apharmaceutical composition to a mammal having a disease, disorder ormedical condition to be treated. In specific embodiments, the mammal isa human. In certain embodiments, therapeutically effective amounts varydepending on the severity of the disease, the age and relative health ofthe subject, the potency of the compound used and other factors. Acompound or salt of Formula (I) or (II) may be used singly or incombination with one or more therapeutic agents as components ofmixtures.

In one embodiment, a compound or salt of Formula (I) or (II) isformulated in an aqueous solution. In specific embodiments, the aqueoussolution is selected from, by way of example only, a physiologicallycompatible buffer, such as Hank's solution, Ringer's solution, orphysiological saline buffer. In other embodiments, a compound or salt ofFormula (I) or (II) is formulated for transmucosal administration. Inspecific embodiments, transmucosal formulations include penetrants thatare appropriate to the barrier to be permeated. In still otherembodiments wherein a compound or salt of Formula (I) or (II) isformulated for other parenteral injections, appropriate formulationsinclude aqueous or nonaqueous solutions. In specific embodiments, suchsolutions include physiologically compatible buffers and/or excipients.

In another embodiment, a compound or salt of Formula (I) or (II) isformulated for oral administration. A compound or salt of Formula (I) or(II) may be formulated by combining the active compounds with, e.g.,pharmaceutically acceptable carriers or excipients. In variousembodiments, a compound or salt of Formula (I) or (II) is formulated inoral dosage forms that include, by way of example only, tablets,powders, pills, dragees, capsules, liquids, gels, syrups, elixirs,slurries, suspensions and the like.

In certain embodiments, pharmaceutical preparations for oral use areobtained by mixing one or more solid excipient with a compound or saltof Formula (I) or (II), optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries,if desired, to obtain tablets or dragee cores. Suitable excipients are,in particular, fillers such as sugars, including lactose, sucrose,mannitol, or sorbitol; cellulose preparations such as: for example,maize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Inspecific embodiments, disintegrating agents are optionally added.Disintegrating agents include, by way of example only, cross-linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate.

In one embodiment, dosage forms, such as dragee cores and tablets, areprovided with one or more suitable coating. In specific embodiments,concentrated sugar solutions are used for coating the dosage form. Thesugar solutions, optionally contain additional components, such as byway of example only, gum arabic, talc, polyvinylpyrrolidone, carbopolgel, polyethylene glycol, and/or titanium dioxide, lacquer solutions,and suitable organic solvents or solvent mixtures. Dyestuffs and/orpigments are also optionally added to the coatings for identificationpurposes. Additionally, the dyestuffs and/or pigments are optionallyutilized to characterize different combinations of active compounddoses.

In certain embodiments, a therapeutically effective amount of a compoundor salt of Formula (I) or (II) is formulated into other oral dosageforms. Oral dosage forms include push-fit capsules made of gelatin, aswell as soft, sealed capsules made of gelatin and a plasticizer, such asglycerol or sorbitol. In specific embodiments, push-fit capsules containthe active ingredients in admixture with one or more filler. Fillersinclude, by way of example only, lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In other embodiments, soft capsules, contain one or moreactive compound that is dissolved or suspended in a suitable liquid.Suitable liquids include, by way of example only, one or more fatty oil,liquid paraffin, or liquid polyethylene glycol. In addition, stabilizersare optionally added.

In other embodiments, a therapeutically effective amount of a compoundor salt of Formula (I) or (II) is formulated for buccal or sublingualadministration. Formulations suitable for buccal or sublingualadministration include, by way of example only, tablets, lozenges, orgels. In still other embodiments, a compound or salt of Formula (I) or(II) is formulated for parental injection, including formulationssuitable for bolus injection or continuous infusion. In specificembodiments, formulations for injection are presented in unit dosageform (e.g., in ampoules) or in multi-dose containers. Preservatives are,optionally, added to the injection formulations. In still otherembodiments, the pharmaceutical compositions are formulated in a formsuitable for parenteral injection as sterile suspensions, solutions oremulsions in oily or aqueous vehicles. Parenteral injection formulationsoptionally contain formulatory agents such as suspending, stabilizingand/or dispersing agents. In specific embodiments, pharmaceuticalformulations for parenteral administration include aqueous solutions ofthe active compounds in water-soluble form. In additional embodiments, asuspension of a compound or salt of Formula (I) or (II) is prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles for use in the pharmaceutical compositions described hereininclude, by way of example only, fatty oils such as sesame oil, orsynthetic fatty acid esters, such as ethyl oleate or triglycerides, orliposomes. In certain specific embodiments, aqueous injectionsuspensions contain substances which increase the viscosity of thesuspension, such as sodium carboxymethyl cellulose, sorbitol, ordextran. Optionally, the suspension contains suitable stabilizers oragents which increase the solubility of the compounds to allow for thepreparation of highly concentrated solutions. In certain embodiments,the active agent is in powder form for constitution with a suitablevehicle, e.g., sterile pyrogen-free water, before use.

In still other embodiments, a compound or salt of Formula (I) or (II) isadministered topically. A compound or salt of Formula (I) or (II) may beformulated into a variety of topically administrable compositions, suchas solutions, suspensions, lotions, gels, pastes, medicated sticks,balms, creams or ointments. Such pharmaceutical compositions optionallycontain solubilizers, stabilizers, tonicity enhancing agents, buffersand preservatives.

In yet other embodiments, a compound or salt of Formula (I) or (II) isformulated for transdermal administration. Transdermal formulations mayemploy transdermal delivery devices and transdermal delivery patches andcan be lipophilic emulsions or buffered, aqueous solutions, dissolvedand/or dispersed in a polymer or an adhesive. In various embodiments,such patches are constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents. In additional embodiments, thetransdermal delivery of a compound or salt of Formula (I) or (II) isaccomplished by means of iontophoretic patches and the like. In certainembodiments, transdermal patches provide controlled delivery of acompound or salt of Formula (I) or (II). In specific embodiments, therate of absorption is slowed by using rate-controlling membranes or bytrapping the compound within a polymer matrix or gel. In alternativeembodiments, absorption enhancers are used to increase absorption.Absorption enhancers or carriers include absorbable pharmaceuticallyacceptable solvents that assist passage through the skin. For example,in one embodiment, transdermal devices are in the form of a bandagecomprising a backing member, a reservoir containing a compound or saltof Formula (I) or (II), optionally with carriers, optionally a ratecontrolling barrier to deliver the compound to the skin of the host at acontrolled and predetermined rate over a prolonged period of time, andmeans to secure the device to the skin.

In other embodiments, a compound or salt of Formula (I) or (II) isformulated for administration by inhalation. Various forms suitable foradministration by inhalation include, but are not limited to, aerosols,mists or powders. Pharmaceutical compositions of a compound or salt ofFormula (I) or (II) are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant (e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas). In specific embodiments, the dosage unit of apressurized aerosol is determined by providing a valve to deliver ametered amount. In certain embodiments, capsules and cartridges of, suchas, by way of example only, gelatin for use in an inhaler or insufflatorare formulated containing a powder mix of a compound or salt of Formula(I) or (II) and a suitable powder base such as lactose or starch.

In still other embodiments, a compound or salt of Formula (I) or (II) isformulated in rectal compositions such as enemas, rectal gels, rectalfoams, rectal aerosols, suppositories, jelly suppositories, or retentionenemas, containing conventional suppository bases such as cocoa butteror other glycerides, as well as synthetic polymers such aspolyvinylpyrrolidone, PEG, and the like. In suppository forms of thecompositions, a low-melting wax such as, but not limited to, a mixtureof fatty acid glycerides, optionally in combination with cocoa butter isfirst melted.

In certain embodiments, pharmaceutical compositions are formulated inany conventional manner using one or more physiologically acceptablecarriers comprising excipients and auxiliaries which facilitateprocessing of the active compounds into preparations which can be usedpharmaceutically. Proper formulation is dependent upon the route ofadministration chosen. Any pharmaceutically acceptable techniques,carriers, and excipients may be optionally used as suitable.Pharmaceutical compositions comprising a compound or salt of Formula (I)or (II) are manufactured in a conventional manner, such as, by way ofexample only, by means of conventional mixing, dissolving, granulating,dragee-making, levigating, emulsifying, encapsulating, entrapping orcompression processes.

Pharmaceutical compositions include at least one pharmaceuticallyacceptable carrier, diluent or excipient and a compound or salt ofFormula (I) or (II), sometimes referred to herein as an active agent oringredient. The active ingredient may be in free-acid or free-base form,or in a pharmaceutically acceptable salt form. Additionally, a compoundor salt of Formula (I) or (II) may be in unsolvated or solvated formswith pharmaceutically acceptable solvents such as water and ethanol. Inaddition, the pharmaceutical compositions optionally include othermedicinal or pharmaceutical agents, carriers, adjuvants, such aspreserving, stabilizing, wetting or emulsifying agents, solutionpromoters, salts for regulating the osmotic pressure, buffers, and/orother therapeutically valuable substances.

Methods for the preparation of compositions comprising a compound orsalt of Formula (I) or (II) include formulating the compounds with oneor more inert, pharmaceutically acceptable excipients or carriers toform a solid, semi-solid or liquid. Solid compositions include, but arenot limited to, powders, tablets, dispersible granules, capsules,cachets, and suppositories. Liquid compositions include solutions inwhich a compound is dissolved, emulsions comprising a compound, or asolution containing liposomes, micelles, or nanoparticles comprising acompound or salt of Formula (I) or (II). Semi-solid compositionsinclude, but are not limited to, gels, suspensions and creams. The formof the pharmaceutical compositions of a compound or salt of Formula (I)or (II) include liquid solutions or suspensions, solid forms suitablefor solution or suspension in a liquid prior to use, or as emulsions.These compositions also optionally contain minor amounts of nontoxic,auxiliary substances, such as wetting or emulsifying agents, pHbuffering agents, and so forth.

In some embodiments, a pharmaceutical composition comprising a compoundor salt of Formula (I) or (II) takes the form of a liquid where theagents are present in solution, in suspension or both. Typically whenthe composition is administered as a solution or suspension a firstportion of the agent is present in solution and a second portion of theagent is present in particulate form, in suspension in a liquid matrix.In some embodiments, a liquid composition includes a gel formulation. Inother embodiments, the liquid composition is aqueous.

In certain embodiments, aqueous suspensions contain one or more polymersas suspending agents. Polymers include water-soluble polymers such ascellulosic polymers, e.g., hydroxypropyl methylcellulose, andwater-insoluble polymers such as cross-linked carboxyl-containingpolymers. Certain pharmaceutical compositions described herein comprisea mucoadhesive polymer, selected for example fromcarboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

Pharmaceutical compositions also, optionally, include solubilizingagents to aid in the solubility of a compound described herein. The term“solubilizing agent” generally includes agents that result in formationof a micellar solution or a true solution of the agent. Certainacceptable nonionic surfactants, for example polysorbate 80, are usefulas solubilizing agents, as can ophthalmically acceptable glycols,polyglycols, e.g., polyethylene glycol 400, and glycol ethers.

Pharmaceutical compositions optionally include one or more pH adjustingagents or buffering agents, including acids such as acetic, boric,citric, lactic, phosphoric and hydrochloric acids; bases such as sodiumhydroxide, sodium phosphate, sodium borate, sodium citrate, sodiumacetate, sodium lactate and tris-hydroxymethylaminomethane; and bufferssuch as citrate/dextrose, sodium bicarbonate and ammonium chloride. Suchacids, bases and buffers are included in an amount required to maintainpH of the composition in an acceptable range.

Additionally, useful compositions also, optionally, include one or moresalts in an amount required to bring osmolality of the composition intoan acceptable range. Such salts include those having sodium, potassiumor ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Pharmaceutical compositions optionally include one or more preservativesto inhibit microbial activity. Suitable preservatives includemercury-containing substances such as merfen and thiomersal; stabilizedchlorine dioxide; and quaternary ammonium compounds such as benzalkoniumchloride, cetyltrimethylammonium bromide and cetylpyridinium chloride.

Pharmaceutical compositions may include one or more surfactants toenhance physical stability or for other purposes. Suitable nonionicsurfactants include polyoxyethylene fatty acid glycerides and vegetableoils, e.g., polyoxyethylene (60) hydrogenated castor oil; andpolyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol 10,octoxynol 40.

Pharmaceutical compositions may include one or more antioxidants toenhance chemical stability where required. Suitable antioxidantsinclude, by way of example only, ascorbic acid and sodium metabisulfite.

In certain embodiments, aqueous suspension compositions are packaged insingle-dose non-reclosable containers. Alternatively, multiple-dosereclosable containers are used, in which case it is typical to include apreservative in the composition.

In certain embodiments, delivery systems for hydrophobic pharmaceuticalcompounds are employed. Liposomes and emulsions are examples of deliveryvehicles or carriers useful herein. In certain embodiments, organicsolvents such as N-methylpyrrolidone are also employed. In additionalembodiments, a compound or salt of Formula (I) or (II) is deliveredusing a sustained-release system, such as semipermeable matrices ofsolid hydrophobic polymers containing the therapeutic agent. Varioussustained-release materials may be used herein. In some embodiments,sustained-release capsules release the compounds for a few weeks up toover 100 days. Depending on the chemical nature and the biologicalstability of the therapeutic reagent, additional strategies for proteinstabilization are employed.

In certain embodiments, the formulations described herein comprise oneor more antioxidants, metal chelating agents, thiol containing compoundsand/or other general stabilizing agents. Examples of such stabilizingagents, include, but are not limited to: (a) about 0.5% to about 2% w/vglycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% toabout 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e)about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/vpolysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h)arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (1)pentosan polysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

In some embodiments, the concentration of a compound or salt of Formula(I) or (II) provided in a pharmaceutical compositions is less thanabout:100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%,15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%,0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%,0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%,0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%,0.0003%, 0.0002%, or 0.0001% w/w, w/v or v/v.

In some embodiments, the concentration of a compound or salt of Formula(I) or (II) provided in a pharmaceutical composition is greater thanabout: 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%,19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%,16.50%, 16.25%, 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%,14.25%, 14%, 13.75%, 13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25%, 12%,11.75%, 11.50%, 11.25%, 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%,9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25%, 7%, 6.75%,6.50%, 6.25%, 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%,3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%,1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%,0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or v/v.

In some embodiments, the concentration of a compound or salt of Formula(I) or (II) is in the range from approximately 0.0001% to approximately50%, approximately 0.001% to approximately 40%, approximately 0.01% toapproximately 30%, approximately 0.02% to approximately 29%,approximately 0.03% to approximately 28%, approximately 0.04% toapproximately 27%, approximately 0.05% to approximately 26%,approximately 0.06% to approximately 25%, approximately 0.07% toapproximately 24%, approximately 0.08% to approximately 23%,approximately 0.09% to approximately 22%, approximately 0.1% toapproximately 21%, approximately 0.2% to approximately 20%,approximately 0.3% to approximately 19%, approximately 0.4% toapproximately 18%, approximately 0.5% to approximately 17%,approximately 0.6% to approximately 16%, approximately 0.7% toapproximately 15%, approximately 0.8% to approximately 14%,approximately 0.9% to approximately 12%, approximately 1% toapproximately 10% w/w, w/v or v/v.

In some embodiments, the concentration of a compound or salt of Formula(I) or (II) is in the range from approximately 0.001% to approximately10%, approximately 0.01% to approximately 5%, approximately 0.02% toapproximately 4.5%, approximately 0.03% to approximately 4%,approximately 0.04% to approximately 3.5%, approximately 0.05% toapproximately 3%, approximately 0.06% to approximately 2.5%,approximately 0.07% to approximately 2%, approximately 0.08% toapproximately 1.5%, approximately 0.09% to approximately 1%,approximately 0.1% to approximately 0.9% w/w, w/v or v/v.

In some embodiments, the amount of a compound or salt of Formula (I) or(II) is equal to or less than about: 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g,7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g,2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g,0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g,0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g,0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

In some embodiments, the amount of a compound or salt of Formula (I) or(II) is more than about: 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g,0.0025 g, 0.003 g, 0.0035 g, 0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g,0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g,0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1g, 1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5g, 7 g,7.5g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

In some embodiments, the amount of one or more compounds of thedisclosure is in the range of 0.0001-10 g, 0.0005-9 g, 0.001-8 g,0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or 1-3 g.

For use in the therapeutic applications described herein, kits andarticles of manufacture are also provided. In some embodiments, suchkits comprise a carrier, package, or container that is compartmentalizedto receive one or more containers such as vials, tubes, and the like,each of the container(s) comprising one of the separate elements to beused in a method described herein. Suitable containers include, forexample, bottles, vials, syringes, and test tubes. The containers areformed from a variety of materials such as glass or plastic.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products includethose found in, e.g., U.S. Pat. Nos. 5,323,907, 5,052,558 and 5,033,252.Examples of pharmaceutical packaging materials include, but are notlimited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials,containers, syringes, bottles, and any packaging material suitable for aselected formulation and intended mode of administration and treatment.For example, the container(s) includes a compound or salt of Formula (I)or (II), optionally in a composition or in combination with anotheragent as disclosed herein. The container(s) optionally have a sterileaccess port (for example the container is an intravenous solution bag ora vial having a stopper pierceable by a hypodermic injection needle).Such kits optionally comprising a compound with an identifyingdescription or label or instructions relating to its use in the methodsdescribed herein.

For example, a kit typically includes one or more additional containers,each with one or more of various materials (such as reagents, optionallyin concentrated form, and/or devices) desirable from a commercial anduser standpoint for use of a compound described herein. Non-limitingexamples of such materials include, but not limited to, buffers,diluents, filters, needles, syringes; carrier, package, container, vialand/or tube labels listing contents and/or instructions for use, andpackage inserts with instructions for use. A set of instructions willalso typically be included. A label is optionally on or associated withthe container. For example, a label is on a container when letters,numbers or other characters forming the label are attached, molded oretched into the container itself, a label is associated with a containerwhen it is present within a receptacle or carrier that also holds thecontainer, e.g., as a package insert. In addition, a label is used toindicate that the contents are to be used for a specific therapeuticapplication. In addition, the label indicates directions for use of thecontents, such as in the methods described herein. In certainembodiments, the pharmaceutical composition is presented in a pack ordispenser device which contains one or more unit dosage forms containinga compound provided herein. The pack, for example, contains metal orplastic foil, such as a blister pack. Or, the pack or dispenser deviceis accompanied by instructions for administration. Or, the pack ordispenser is accompanied with a notice associated with the container inform prescribed by a governmental agency regulating the manufacture,use, or sale of pharmaceuticals, which notice is reflective of approvalby the agency of the form of the drug for human or veterinaryadministration. Such notice, for example, is the labeling approved bythe U.S. Food and Drug Administration for prescription drugs, or theapproved product insert. In some embodiments, compositions containing acompound provided herein formulated in a compatible pharmaceuticalcarrier are prepared, placed in an appropriate container, and labeledfor treatment of an indicated condition.

Methods

The present disclosure provides a method of inhibiting the interactionof menin and one or more proteins (e.g., MLL1, MLL2, an MLL fusionprotein, or an MLL Partial Tandem Duplication) comprising contacting acell with an effective amount of a compound or salt of Formula (I) or(II). Inhibition of the interaction of menin and one or more proteins(e.g., MLL1, MLL2, an MLL fusion protein, or an MLL Partial TandemDuplication) can be assessed and demonstrated by a wide variety of waysknown in the art. Non-limiting examples include a showing of (a) adecrease in menin binding to one or more proteins or protein fragments(e.g., MLL1, MLL2, an MLL fusion protein, an MLL Partial TandemDuplication, or a peptide fragment thereof); (b) a decrease in cellproliferation and/or cell viability; (c) an increase in celldifferentiation; (d) a decrease in the levels of downstream targets ofMLL1, MLL2, an MLL fusion protein, and/or an MLL Partial TandemDuplication (e.g., Hoxa9, DLX2, and Meisl); and/or (e) decrease in tumorvolume and/or tumor volume growth rate. Kits and commercially availableassays can be utilized for determining one or more of the above.

The disclosure also provides methods of using the compounds orpharmaceutical compositions of the present disclosure to treat diseaseconditions, including but not limited to conditions implicated by menin,MLL, MLL1, MLL2, and/or MLL fusion proteins (e.g., cancer).

In some embodiments, a method for treatment of cancer is provided, themethod comprising administering an effective amount of any of theforegoing pharmaceutical compositions comprising a compound or salt ofFormula (I) or (II) to a subject in need thereof. In some embodiments,the cancer is mediated by an MLL fusion protein. In other embodiments,the cancer is leukemia, breast cancer, prostate cancer, pancreaticcancer, lung cancer, liver cancer, skin cancer, or a brain tumor. Incertain embodiments, the cancer is leukemia. In some embodiments, thecancer comprises a solid tumor.

In some embodiments, the disclosure provides a method of treating adisorder in a subject in need thereof, wherein the method comprisesdetermining if the subject has an MLL fusion protein and, if the subjectis determined to have an MLL fusion protein, administering to thesubject a therapeutically effective dose of a compound or salt ofFormula (I) or (II).

MLL fusion proteins have also been identified in hematologicalmalignancies (e.g., cancers that affect blood, bone marrow and/or lymphnodes). Accordingly, certain embodiments are directed to administrationof a compound or salt of Formula (I) or (II) to a patient in need oftreatment of a hematological malignancy. Such malignancies include, butare not limited to leukemias and lymphomas. For example, the presentlydisclosed compounds can be used for treatment of diseases such as Acutelymphoblastic leukemia (ALL), Acute myelogenous leukemia (AML), Chroniclymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), Chronicmyelogenous leukemia (CML), Acute monocytic leukemia (AMoL), hairy cellleukemia, and/or other leukemias. In other embodiments, the compoundsare can be used for treatment of lymphomas such as all subtypes ofHodgkins lymphoma or non-Hodgkins lymphoma.

Determining whether a tumor or cancer comprises an MLL fusion proteincan be undertaken by assessing the nucleotide sequence encoding the MLLfusion protein, by assessing the amino acid sequence of the MLL fusionprotein, or by assessing the characteristics of a putative MLL fusionprotein.

Methods for detecting an MLL fusion protein nucleotide sequence areknown by those of skill in the art. These methods include, but are notlimited to, polymerase chain reaction-restriction fragment lengthpolymorphism (PCR-RFLP) assays, polymerase chain reaction-single strandconformation polymorphism (PCR-SSCP) assays, real-time PCR assays, PCRsequencing, mutant allele-specific PCR amplification (MASA) assays,direct sequencing, primer extension reactions, electrophoresis,oligonucleotide ligation assays, hybridization assays, TaqMan assays,SNP genotyping assays, high resolution melting assays and microarrayanalyses. In some embodiments, the MLL fusion protein is identifiedusing a direct sequencing method of specific regions (e.g., exon 2and/or exon 3) in the MLL or fusion partner gene, for example. Thistechnique will identify all possible mutations in the region sequenced.

Methods for detecting an MLL fusion protein are known by those of skillin the art. These methods include, but are not limited to, detection ofan MLL fusion protein using a binding agent (e.g., an antibody) specificfor the fusion protein, protein electrophoresis and Western blotting,and direct peptide sequencing.

Methods for determining whether a tumor or cancer comprises an MLLfusion protein can use a variety of samples. In some embodiments, thesample is taken from a subject having a tumor or cancer. In someembodiments, the sample is taken from a subject having a cancer ortumor. In some embodiments, the sample is a fresh tumor/cancer sample.In some embodiments, the sample is a frozen tumor/cancer sample. In someembodiments, the sample is a formalin-fixed paraffin-embedded sample. Insome embodiments, the sample is processed to a cell lysate. In someembodiments, the sample is processed to DNA or RNA.

The disclosure also relates to a method of treating a hyperproliferativedisorder in a mammal that comprises administering to the mammal atherapeutically effective amount of a compound or salt of Formula (I) or(II). In some embodiments, the method relates to the treatment of cancersuch as acute myeloid leukemia, cancer in adolescents, adrenocorticalcarcinoma childhood, AIDS-related cancers (e.g., Lymphoma and Kaposi'sSarcoma), anal cancer, appendix cancer, astrocytomas, atypical teratoid,basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer,brain stem glioma, brain tumor, breast cancer, bronchial tumors, burkittlymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germcell tumor, primary lymphoma, cervical cancer, childhood cancers,chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (CML), chronic myleoproliferative disorders, coloncancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNScancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor,extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone,gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumors (GIST), germ cell tumor, gestationaltrophoblastic tumor, hairy cell leukemia, head and neck cancer, heartcancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, islet cell tumors, pancreatic neuroendocrinetumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer,liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma,metastatic squamous neck cancer with occult primary, midline tractcarcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiplemyeloma/plasma cell neoplasm, mycosis fungoides, myelodysplasticsyndromes, myelodysplastic/myeloproliferative neoplasms, multiplemyeloma, merkel cell carcinoma, malignant mesothelioma, malignantfibrous histiocytoma of bone and osteosarcoma, nasal cavity andparanasal sinus cancer, nasopharyngeal cancer, neuroblastoma,non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer,lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer,pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pharyngealcancer, pleuropulmonary blastoma, primary central nervous system (CNS)lymphoma, prostate cancer, rectal cancer, transitional cell cancer,retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer,stomach (gastric) cancer, small cell lung cancer, small intestinecancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throatcancer, thymoma and thymic carcinoma, thyroid cancer, transitional cellcancer of the renal pelvis and ureter, trophoblastic tumor, unusualcancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer,vulvar cancer, or Viral-Induced cancer. In some embodiments, the methodrelates to the treatment of a non-cancerous hyperproliferative disordersuch as benign hyperplasia of the skin (e.g., psoriasis), restenosis, orprostate (e.g., benign prostatic hypertrophy (BPH)). In some cases, themethod relates to the treatment of leukemia, hematologic malignancy,solid tumor cancer, prostate cancer (e.g., castration-resistant prostatecancer), breast cancer, Ewing's sarcoma, bone sarcoma, primary bonesarcoma, T-cell prolymphocyte leukemia, glioma, glioblastoma, livercancer (e.g., hepatocellular carcinoma), or diabetes. In some cases, theleukemia comprises AML, ALL, Mixed Lineage Leukemia or leukemias withPartial Tandem Duplications of MLL.

In certain particular embodiments, the disclosure relates to methods fortreatment of lung cancers, the methods comprise administering aneffective amount of any of the above described compound (or apharmaceutical composition comprising the same) to a subject in needthereof. In certain embodiments the lung cancer is a non-small cell lungcarcinoma (NSCLC), for example adenocarcinoma, squamous-cell lungcarcinoma or large-cell lung carcinoma. In other embodiments, the lungcancer is a small cell lung carcinoma. Other lung cancers treatable withthe disclosed compounds include, but are not limited to, glandulartumors, carcinoid tumors and undifferentiated carcinomas.

Subjects that can be treated with a compound of the disclosure, or apharmaceutically acceptable salt, ester, prodrug, solvate, tautomer,stereoisomer, isotopologue, hydrate or derivative of the compound,according to the methods of this disclosure include, for example,subjects that have been diagnosed as having acute myeloid leukemia,acute myeloid leukemia, cancer in adolescents, adrenocortical carcinomachildhood, AIDS-related cancers (e.g., Lymphoma and Kaposi's Sarcoma),anal cancer, appendix cancer, astrocytomas, atypical teratoid, basalcell carcinoma, bile duct cancer, bladder cancer, bone cancer, brainstem glioma, brain tumor, breast cancer, bronchial tumors, burkittlymphoma, carcinoid tumor, atypical teratoid, embryonal tumors, germcell tumor, primary lymphoma, cervical cancer, childhood cancers,chordoma, cardiac tumors, chronic lymphocytic leukemia (CLL), chronicmyelogenous leukemia (CML), chronic myleoproliferative disorders, coloncancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma,extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, CNScancer, endometrial cancer, ependymoma, esophageal cancer,esthesioneuroblastoma, ewing sarcoma, extracranial germ cell tumor,extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone,gall bladder cancer, gastric cancer, gastrointestinal carcinoid tumor,gastrointestinal stromal tumors (GIST), germ cell tumor, gestationaltrophoblastic tumor, hairy cell leukemia, head and neck cancer, heartcancer, liver cancer, hodgkin lymphoma, hypopharyngeal cancer,intraocular melanoma, islet cell tumors, pancreatic neuroendocrinetumors, kidney cancer, laryngeal cancer, lip and oral cavity cancer,liver cancer, lobular carcinoma in situ (LCIS), lung cancer, lymphoma,metastatic squamous neck cancer with occult primary, midline tractcarcinoma, mouth cancer multiple endocrine neoplasia syndromes, multiplemyeloma/plasma cell neoplasm, mycosis fungoides, myelodysplasticsyndromes, myelodysplastic/myeloproliferative neoplasms, multiplemyeloma, merkel cell carcinoma, malignant mesothelioma, malignantfibrous histiocytoma of bone and osteosarcoma, nasal cavity andparanasal sinus cancer, nasopharyngeal cancer, neuroblastoma,non-hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cancer,lip and oral cavity cancer, oropharyngeal cancer, ovarian cancer,pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus andnasal cavity cancer, parathyroid cancer, penile cancer, pharyngealcancer, pleuropulmonary blastoma, primary central nervous system (CNS)lymphoma, prostate cancer, rectal cancer, transitional cell cancer,retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer,stomach (gastric) cancer, small cell lung cancer, small intestinecancer, soft tissue sarcoma, T-Cell lymphoma, testicular cancer, throatcancer, thymoma and thymic carcinoma, thyroid cancer, transitional cellcancer of the renal pelvis and ureter, trophoblastic tumor, unusualcancers of childhood, urethral cancer, uterine sarcoma, vaginal cancer,vulvar cancer, Viral-Induced cancer, leukemia, hematologic malignancy,solid tumor cancer, prostate cancer, castration-resistant prostatecancer, breast cancer, Ewing's sarcoma, bone sarcoma, primary bonesarcoma, T-cell prolymphocyte leukemia, glioma, glioblastoma,hepatocellular carcinoma, liver cancer, or diabetes. In some embodimentssubjects that are treated with the compounds of the disclosure includesubjects that have been diagnosed as having a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin(e.g., psoriasis), restenosis, or prostate (e.g., benign prostatichypertrophy (BPH)).

The disclosure further provides methods of modulating the interaction ofmenin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein,or an MLL Partial Tandem Duplication) by contacting the menin with aneffective amount of a compound or salt of Formula (I) or (II).Modulation can be inhibiting or activating protein activity of menin,one or more of its binding partners, and/or one or more of thedownstream targets of menin or one or more of its binding partners. Insome embodiments, the disclosure provides methods of inhibiting theinteraction of menin and one or more proteins (e.g., MLL1, MLL2, an MLLfusion protein, or an MLL Partial Tandem Duplication) by contactingmenin with an effective amount of a compound or salt of Formula (I) or(II). In some embodiments, the disclosure provides methods of inhibitingthe interaction of menin and one or more proteins (e.g., MLL1, MLL2, anMLL fusion protein, or an MLL Partial Tandem Duplication) by contactinga cell, tissue, or organ that expresses menin, MLL1, MLL2, an MLL fusionprotein, and/or an MLL Partial Tandem Duplication. In some embodiments,the disclosure provides methods of inhibiting protein activity insubject including but not limited to rodents and mammal (e.g., human) byadministering to the subject an effective amount of a compound or saltof Formula (I) or (II). In some embodiments, the percentage modulationexceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%. In some embodiments,the percentage of inhibiting exceeds 25%, 30%, 40%, 50%, 60%, 70%, 80%,or 90%.

In some embodiments, the disclosure provides methods of inhibiting theinteraction of menin and one or more proteins (e.g., MLL1, MLL2, an MLLfusion protein, or an MLL Partial Tandem Duplication) in a cell bycontacting the cell with an amount of a compound of the disclosuresufficient to inhibit the interaction of menin and one or more proteins(e.g., MLL1, MLL2, an MLL fusion protein, or an MLL Partial TandemDuplication) in the cell. In some embodiments, the disclosure providesmethods of inhibiting the interaction of menin and one or more proteins(e.g., MLL1, MLL2, an MLL fusion protein, or an MLL Partial TandemDuplication) in a tissue by contacting the tissue with an amount of acompound or salt of Formula (I) or (II) sufficient to inhibit theinteraction of menin and one or more proteins (e.g., MLL1, MLL2, an MLLfusion protein, or an MLL Partial Tandem Duplication) in the tissue. Insome embodiments, the disclosure provides methods of inhibiting theinteraction of menin and one or more proteins (e.g., MLL1, MLL2, an MLLfusion protein, or an MLL Partial Tandem Duplication) in an organism bycontacting the organism with an amount of a compound or salt of Formula(I) or (II) sufficient to inhibit the interaction of menin and one ormore proteins (e.g., MLL1, MLL2, an MLL fusion protein, or an MLLPartial Tandem Duplication) in the organism. In some embodiments, thedisclosure provides methods of inhibiting the interaction of menin andone or more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or an MLLPartial Tandem Duplication) in an animal by contacting the animal withan amount of a compound of the disclosure sufficient to inhibit theinteraction of menin and one or more proteins (e.g., MLL1, MLL2, an MLLfusion protein, or an MLL Partial Tandem Duplication) in the animal Insome embodiments, the disclosure provides methods of inhibiting theinteraction of menin and one or more proteins (e.g., MLL1, MLL2, an MLLfusion protein, or an MLL Partial Tandem Duplication) in a mammal bycontacting the mammal with an amount of a compound of the disclosuresufficient to inhibit the interaction of menin and one or more proteins(e.g., MLL1, MLL2, an MLL fusion protein, or an MLL Partial TandemDuplication) in the mammal. In some embodiments, the disclosure providesmethods of inhibiting the interaction of menin and one or more proteins(e.g., MLL1, MLL2, an MLL fusion protein, or an MLL Partial TandemDuplication) in a human by contacting the human with an amount of acompound of the disclosure sufficient to inhibit the interaction ofmenin and one or more proteins (e.g., MLL1, MLL2, an MLL fusion protein,or an MLL Partial Tandem Duplication) in the human. The presentdisclosure provides methods of treating a disease mediated by theinteraction of menin and one or more proteins (e.g., MLL1, MLL2, an MLLfusion protein, or an MLL Partial Tandem Duplication) in a subject inneed of such treatment.

The disclosure also provides methods of treating a disorder mediated bymenin interaction with one or more proteins (e.g., MLL1, MLL2, an MLLfusion protein, or an MLL Partial Tandem Duplication) by administeringto a subject in need thereof a therapeutically effective amount of acompound or salt of Formula (I) or (II).

The disclosure further provides methods of treating a disorder mediatedby chromosomal rearrangement on chromosome 11q23 in a subject in needthereof by administering to the subject a therapeutically effectiveamount of a compound or salt of Formula (I) or (II).

The disclosure also provides methods for the treatment of a disease orcondition by administering an effective amount of a compound or salt ofFormula (I) or (II) to a subject suffering from the disease orcondition.

The disclosure further provides methods for the treatment of a diseaseor condition by administering a compound or salt of Formula (I) or (II)to a subject suffering from the disease or condition, wherein thecompound binds to menin and inhibits the interaction of menin with oneor more proteins (e.g., MLL1, MLL2, an MLL fusion protein, or an MLLPartial Tandem Duplication).

The disclosure further provides methods of stabilizing menin, comprisingcontacting menin with a compound or salt of Formula (I) or (II). In someembodiments, the contacting step comprises contacting menin with anamount of the compound sufficient to stabilize menin. In someembodiments, the contacting step takes place in vivo. In someembodiments, the contacting step takes place in vitro. In someembodiments, the contacting step takes place in a cell.

The present disclosure also provides methods for combination therapiesin which an agent known to modulate other pathways, or other componentsof the same pathway, or even overlapping sets of target enzymes are usedin combination with a compound or salt of Formula (I) or (II). In oneaspect, such therapy includes but is not limited to the combination ofone or more compounds of the disclosure with chemotherapeutic agents,therapeutic antibodies, and radiation treatment, to provide asynergistic or additive therapeutic effect.

Where desired, a compound or pharmaceutical composition of the presentdisclosure can be used in combination with Notch inhibitors and/or c-Mybinhibitors. Where desired, a compound or pharmaceutical composition ofthe present disclosure can be used in combination with MLL-WDR5inhibitors and/or Dotll inhibitors.

Many chemotherapeutics are presently known in the art and can be used incombination with a compound of the disclosure. In some embodiments, thechemotherapeutic is selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,angiogenesis inhibitors, and anti-androgens.

Non-limiting examples are chemotherapeutic agents, cytotoxic agents, andnon-peptide small molecules such as Gleevec® (Imatinib Mesylate),Velcade® (bortezomib), Casodex (bicalutamide), Iressa® (gefitinib), andAdriamycin as well as a host of chemotherapeutic agents. Non-limitingexamples of chemotherapeutic agents include alkylating agents such asthiotepa and cyclosphosphamide (CYTOXAN™); alkyl sulfonates such asbusulfan, improsulfan and piposulfan; aziridines such as benzodopa,carboquone, meturedopa, and uredopa; ethylenimines and methylamelaminesincluding altretamine, triethylenemelamine, trietylenephosphoramide,triethylenethiophosphaoramide and trimethylolomelamine; nitrogenmustards such as chlorambucil, chlornaphazine, cholophosphamide,estramustine, ifosfamide, mechlorethamine, mechlorethamine oxidehydrochloride, melphalan, novembichin, phenesterine, prednimustine,trofosfamide, uracil mustard; nitrosureas such as carmustine,chlorozotocin, fotemustine, lomustine, nimustine, ranimustine;antibiotics such as aclacinomysins, actinomycin, authramycin, azaserine,bleomycins, cactinomycin, calicheamicin, carabicin, carminomycin,carzinophilin, Casodex™, chromomycins, dactinomycin, daunorubicin,detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin, epirubicin,esorubicin, idarubicin, marcellomycin, mitomycins, mycophenolic acid,nogalamycin, olivomycins, peplomycin, potfiromycin, puromycin,quelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin,ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexateand 5-fluorouracil (5-FU); folic acid analogues such as denopterin,methotrexate, pteropterin, trimetrexate; purine analogs such asfludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,androgens such as calusterone, dromostanolone propionate, epitiostanol,mepitiostane, testolactone; anti-adrenals such as aminoglutethimide,mitotane, trilostane; folic acid replenisher such as frolinic acid;aceglatone; aldophosphamide glycoside; aminolevulinic acid; amsacrine;bestrabucil; bisantrene; edatraxate; defofamine; demecolcine;diaziquone; elfomithine; elliptinium acetate; etoglucid; galliumnitrate; hydroxyurea; lentinan; lonidamine; mitoguazone; mitoxantrone;mopidamol; nitracrine; pentostatin; phenamet; pirarubicin; podophyllinicacid; 2-ethylhydrazide; procarbazine; PSK.RTM.; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (“Ara-C”); cyclophosphamide; thiotepa; taxanes, e.g.,paclitaxel (TAXOL™, Bristol-Myers Squibb Oncology, Princeton, N.J.) anddocetaxel (TAXOTERE™, Rhone-Poulenc Rorer, Antony, France); retinoicacid; esperamicins; capecitabine; and pharmaceutically acceptable salts,acids or derivatives of any of the above. Also included as suitablechemotherapeutic cell conditioners are anti-hormonal agents that act toregulate or inhibit hormone action on tumors such as anti-estrogensincluding for example tamoxifen, (Nolvadex™), raloxifene, aromataseinhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene,LY 117018, onapristone, and toremifene (Fareston); and anti-androgenssuch as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin;chlorambucil; gemcitabine; 6-thioguanine; mercaptopurine; methotrexate;platinum analogs such as cisplatin and carboplatin; vinblastine;platinum; etoposide (VP-16); ifosfamide; mitomycin C; mitoxantrone;vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin;aminopterin; xeloda; ibandronate; camptothecin-11 (CPT-11);topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO). Wheredesired, the compounds or pharmaceutical composition of the presentdisclosure can be used in combination with commonly prescribedanti-cancer drugs such as Herceptin®, Avastin®, Erbitux®, Rituxan®,Taxol®, Arimidex®, Taxotere®, ABVD, AVICINE, Abagovomab, Acridinecarboxamide, Adecatumumab, 17-N-Allylamino-17-demethoxygeldanamycin,Alpharadin, Alvocidib, 3-Aminopyridine-2-carboxaldehydethiosemicarbazone, Amonafide, Anthracenedione, Anti-CD22 immunotoxins,Antineoplastic, Antitumorigenic herbs, Apaziquone, Atiprimod,Azathioprine, Belotecan, Bendamustine, BIBW 2992, Biricodar,Brostallicin, Bryostatin, Buthionine sulfoximine, CBV (chemotherapy),Calyculin, cell-cycle nonspecific antineoplastic agents, Dichloroaceticacid, Discodermolide, Elsamitrucin, Enocitabine, Epothilone, Eribulin,Everolimus, Exatecan, Exisulind, Ferruginol, Forodesine, Fosfestrol, ICEchemotherapy regimen, IT-101, Imexon, Imiquimod, Indolocarbazole,Irofulven, Laniquidar, Larotaxel, Lenalidomide, Lucanthone, Lurtotecan,Mafosfamide, Mitozolomide, Nafoxidine, Nedaplatin, Olaparib, Ortataxel,PAC-1, Pawpaw, Pixantrone, Proteasome inhibitor, Rebeccamycin,Resiquimod, Rubitecan, SN-38, Salinosporamide A, Sapacitabine, StanfordV, Swainsonine, Talaporfin, Tariquidar, Tegafur-uracil, Temodar,Tesetaxel, Triplatin tetranitrate, Tris(2-chloroethyl)amine,Troxacitabine, Uramustine, Vadimezan, Vinflunine, ZD6126 or Zosuquidar.

This disclosure further relates to a method for using a compound or saltof Formula (I) or (II) or a pharmaceutical composition provided herein,in combination with radiation therapy for inhibiting abnormal cellgrowth or treating the hyperproliferative disorder in the mammal.Techniques for administering radiation therapy are known in the art, andthese techniques can be used in the combination therapy describedherein. The administration of the compound of the disclosure in thiscombination therapy can be determined as described herein.

Radiation therapy can be administered through one of several methods, ora combination of methods, including without limitation external-beamtherapy, internal radiation therapy, implant radiation, stereotacticradiosurgery, systemic radiation therapy, radiotherapy and permanent ortemporary interstitial brachytherapy. The term “brachytherapy,” as usedherein, refers to radiation therapy delivered by a spatially confinedradioactive material inserted into the body at or near a tumor or otherproliferative tissue disease site. The term is intended withoutlimitation to include exposure to radioactive isotopes (e.g., At-211,I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, andradioactive isotopes of Lu). Suitable radiation sources for use as acell conditioner of the present disclosure include both solids andliquids. By way of non-limiting example, the radiation source can be aradionuclide, such as I-125, I-131, Yb-169, Ir-192 as a solid source,I-125 as a solid source, or other radionuclides that emit photons, betaparticles, gamma radiation, or other therapeutic rays. The radioactivematerial can also be a fluid made from any solution of radionuclide(s),e.g., a solution of I-125 or I-131, or a radioactive fluid can beproduced using a slurry of a suitable fluid containing small particlesof solid radionuclides, such as Au-198, Y-90. Moreover, theradionuclide(s) can be embodied in a gel or radioactive micro spheres.

The compounds or pharmaceutical compositions of the disclosure can beused in combination with an amount of one or more substances selectedfrom anti-angiogenesis agents, signal transduction inhibitors,antiproliferative agents, glycolysis inhibitors, or autophagyinhibitors.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-11(cyclooxygenase 11) inhibitors, can be used in conjunction with acompound of the disclosure and pharmaceutical compositions describedherein. Anti-angiogenesis agents include, for example, rapamycin,temsirolimus (CCI-779), everolimus (RAD001), sorafenib, sunitinib, andbevacizumab. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24,1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13,1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931, 788 (published Jul. 28, 1999), WO90/05719 (published May 31,1990), WO 99/52910 (published Oct. 21,1999),WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (published Jun.17,1999), PCT International Application No. PCT/IB98/01113 (filed Jul.21, 1998), European Patent Application No. 99302232.1 (filed Mar. 25,1999), Great Britain Patent Application No. 9912961.1 (filed Jun. 3,1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26,1999), U.S. Pat. No.5,861, 510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. Preferred MMP-2 and MMP-9 inhibitorsare those that have little or no activity inhibiting MMP-1. Morepreferred, are those that selectively inhibit MMP-2 and/or AMP-9relative to the other matrix-metalloproteinases (e.g., MAP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, MMP-12, andMMP-13).Some specific examples of MMP inhibitors useful in the disclosure areAG-3340, RO 32-3555, and RS 13-0830.

Autophagy inhibitors include, but are not limited to chloroquine,3-methyladenine, hydroxychloroquine (Plaquenil™), bafilomycin A1,5-amino-4-imidazole carboxamide riboside (AICAR), okadaic acid,autophagy-suppressive algal toxins which inhibit protein phosphatases oftype 2A or type 1, analogues of cAMP, and drugs which elevate cAMPlevels such as adenosine, LY204002, N6-mercaptopurine riboside, andvinblastine. In addition, antisense or siRNA that inhibits expression ofproteins including but not limited to ATG5 (which are implicated inautophagy), may also be used.

In some embodiments, the compounds described herein are formulated oradministered in conjunction with liquid or solid tissue barriers alsoknown as lubricants. Examples of tissue barriers include, but are notlimited to, polysaccharides, polyglycans, seprafilm, interceed andhyaluronic acid.

In some embodiments, medicaments which are administered in conjunctionwith the compounds described herein include any suitable drugs usefullydelivered by inhalation for example, analgesics, e.g., codeine,dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations,e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen ornedocromil; anti-infectives, e.g., cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines or pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone, flunisolide, budesonide, tipredane, triamcinoloneacetonide or fluticasone; antitussives, e.g., noscapine;bronchodilators, e.g., ephedrine, adrenaline, fenoterol, formoterol,isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol, reproterol, rimiterol, salbutamol, salmeterol, terbutalin,isoetharine, tulobuterol, orciprenaline or(−)-4-amino-3,5-dichloro-α-[[[6-[2-(2-pyridinyl)ethoxy]hexyl]-amino]methyl]benzenemethanol;diuretics, e.g., amiloride; anticholinergics e.g., ipratropium, atropineor oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; and therapeutic proteins andpeptides, e.g., insulin or glucagon. It will be clear to a personskilled in the art that, where appropriate, the medicaments are used inthe form of salts (e.g., as alkali metal or amine salts or as acidaddition salts) or as esters (e.g., lower alkyl esters) or as solvates(e.g., hydrates) to optimize the activity and/or stability of themedicament.

Other exemplary therapeutic agents useful for a combination therapyinclude but are not limited to agents as described above, radiationtherapy, hormone antagonists, hormones and their releasing factors,thyroid and antithyroid drugs, estrogens and progestins, androgens,adrenocorticotropic hormone; adrenocortical steroids and their syntheticanalogs; inhibitors of the synthesis and actions of adrenocorticalhormones, insulin, oral hypoglycemic agents, and the pharmacology of theendocrine pancreas, agents affecting calcification and bone turnover:calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitaminssuch as water-soluble vitamins, vitamin B complex, ascorbic acid,fat-soluble vitamins, vitamins A, K, and E, growth factors, cytokines,chemokines, muscarinic receptor agonists and antagonists;anticholinesterase agents; agents acting at the neuromuscular junctionand/or autonomic ganglia; catecholamines, sympathomimetic drugs, andadrenergic receptor agonists or antagonists; and 5-hydroxytryptamine(5-HT, serotonin) receptor agonists and antagonists.

Therapeutic agents can also include agents for pain and inflammationsuch as histamine and histamine antagonists, bradykinin and bradykininantagonists, 5-hydroxytryptamine (serotonin), lipid substances that aregenerated by biotransformation of the products of the selectivehydrolysis of membrane phospholipids, eicosanoids, prostaglandins,thromboxanes, leukotrienes, aspirin, nonsteroidal anti-inflammatoryagents, analgesic-antipyretic agents, agents that inhibit the synthesisof prostaglandins and thromboxanes, selective inhibitors of theinducible cyclooxygenase, selective inhibitors of the induciblecyclooxygenase-2, autacoids, paracrine hormones, somatostatin, gastrin,cytokines that mediate interactions involved in humoral and cellularimmune responses, lipid-derived autacoids, eicosanoids, β-adrenergicagonists, ipratropium, glucocorticoids, methylxanthines, sodium channelblockers, opioid receptor agonists, calcium channel blockers, membranestabilizers and leukotriene inhibitors.

Additional therapeutic agents contemplated herein include diuretics,vasopressin, agents affecting the renal conservation of water, rennin,angiotensin, agents useful in the treatment of myocardial ischemia,anti-hypertensive agents, angiotensin converting enzyme inhibitors,β-adrenergic receptor antagonists, agents for the treatment ofhypercholesterolemia, and agents for the treatment of dyslipidemia.

Other therapeutic agents contemplated include drugs used for control ofgastric acidity, agents for the treatment of peptic ulcers, agents forthe treatment of gastroesophageal reflux disease, prokinetic agents,antiemetics, agents used in irritable bowel syndrome, agents used fordiarrhea, agents used for constipation, agents used for inflammatorybowel disease, agents used for biliary disease, agents used forpancreatic disease. Therapeutic agents used to treat protozoaninfections, drugs used to treat Malaria, Amebiasis, Giardiasis,Trichomoniasis, Trypanosomiasis, and/or Leishmaniasis, and/or drugs usedin the chemotherapy of helminthiasis. Other therapeutic agents includeantimicrobial agents, sulfonamides, trimethoprim-sulfamethoxazolequinolones, and agents for urinary tract infections, penicillins,cephalosporins, and other, β-lactam antibiotics, an agent comprising anaminoglycoside, protein synthesis inhibitors, drugs used in thechemotherapy of tuberculosis, mycobacterium avium complex disease, andleprosy, antifungal agents, antiviral agents including nonretroviralagents and antiretroviral agents.

Examples of therapeutic antibodies that can be combined with a compoundof the disclosure include but are not limited to anti-receptor tyrosinekinase antibodies (cetuximab, panitumumab, trastuzumab), anti CD20antibodies (rituximab, tositumomab), and other antibodies such asalemtuzumab, bevacizumab, and gemtuzumab.

Moreover, therapeutic agents used for immunomodulation, such asimmunomodulators, immunosuppressive agents, tolerogens, andimmunostimulants are contemplated by the methods herein. In addition,therapeutic agents acting on the blood and the blood-forming organs,hematopoietic agents, growth factors, minerals, and vitamins,anticoagulant, thrombolytic, and antiplatelet drugs.

For treating renal carcinoma, one may combine a compound of the presentdisclosure with sorafenib and/or avastin. For treating an endometrialdisorder, one may combine a compound of the present disclosure withdoxorubincin, taxotere (taxol), and/or cisplatin (carboplatin). Fortreating ovarian cancer, one may combine a compound of the presentdisclosure with cisplatin (carboplatin), taxotere, doxorubincin,topotecan, and/or tamoxifen. For treating breast cancer, one may combinea compound of the present disclosure with taxotere (taxol), gemcitabine(capecitabine), tamoxifen, letrozole, tarceva, lapatinib, PD0325901,avastin, herceptin, OSI-906, and/or OSI-930. For treating lung cancer,one may combine a compound of the present disclosure with taxotere(taxol), gemcitabine, cisplatin, pemetrexed, Tarceva, PD0325901, and/oravastin.

Further therapeutic agents that can be combined with a compound of thedisclosure are found in Goodman and Gilman's “The Pharmacological Basisof Therapeutics” Tenth Edition edited by Hardman, Limbird and Gilman orthe Physician's Desk Reference, both of which are incorporated herein byreference in their entirety.

The compounds described herein can be used in combination with theagents disclosed herein or other suitable agents, depending on thecondition being treated. Hence, in some embodiments the one or morecompounds of the disclosure will be co-administered with other agents asdescribed above. When used in combination therapy, the compoundsdescribed herein are administered with the second agent simultaneouslyor separately. This administration in combination can includesimultaneous administration of the two agents in the same dosage form,simultaneous administration in separate dosage forms, and separateadministration. That is, a compound described herein and any of theagents described above can be formulated together in the same dosageform and administered simultaneously. Alternatively, a compound of thedisclosure and any of the agents described above can be simultaneouslyadministered, wherein both the agents are present in separateformulations. In another alternative, a compound of the presentdisclosure can be administered just followed by and any of the agentsdescribed above, or vice versa. In some embodiments of the separateadministration protocol, a compound of the disclosure and any of theagents described above are administered a few minutes apart, or a fewhours apart, or a few days apart.

The following examples are given for the purpose of illustrating variousembodiments of the disclosure and are not meant to limit the presentdisclosure in any fashion. The present examples, along with the methodsand compositions described herein, are presently representative ofpreferred embodiments, are exemplary, and are not intended aslimitations on the scope of the disclosure. Changes therein and otheruses which are encompassed within the spirit of the disclosure asdefined by the scope of the claims will occur to those skilled in theart.

EXAMPLES

Example 1: Synthesis of Compound 59 in Table 1.

Step A: Preparation of Compound 59-2: To a solution ofethyl-2-(diethoxylphosphoryl) acetate (1.91 g, 8.5 mmol) in THF (30 mL)was added NaH (421 mg, 10.5 mmol) at 0° C. The reaction was stirred at0° C. for 0.5 hour before 59-1 (2 g, 8 mmol) was added. The reactionmixture was stirred at room temperature for 5h. Ice-water (50 mL) wasadded, and the product extracted with ethyl acetate (50 mL×2). Thecombined organic layer was washed with brine (50 mL), dried over sodiumsulfate and concentrated in vacuo. The residue was purified by flashchromatography (eluted 20% EtOAc in pet. ether) to afford 2.15 g of 59-2as a white solid (yield: 85%).

Step B: Preparation of Compound 59-3: To a solution of 59-2 (905 mg,2.85 mmol) in MeOH (20 mL) was added (Boc)₂O (1.24 g, 5.71 mmol) andPd/C catalyst. The reaction mixture was stirred at room temperature for8 hours under Hz. TLC showed the reaction was complete. The reaction wasfiltered and concentrated. The residue was purified by silica gel columnchromatography (eluted 20% EtOAc in pet. ether) to give 59-3 as a solid(740 mg, yield: 91%).

Step C: Preparation of Compound 59-4: To a solution of 59-3 (670 mg,2.35 mmol) in THF (20 mL) was added LiAlH₄ (179 mg, 4.7 mmol) at 0° C.The reaction was stirred at 0° C. for 2 h, then 0.2 mL H₂O, 0.2 mL 15%NaOH, and 0.5 mL H₂O added. The mixture was stirred at room temperaturefor 1 h. The mixture was filtered and the organic solution wasconcentrated. The residue was purified by silica gel columnchromatography (eluted 40% EtOAc in pet. ether) to give 59-4 as a solid(525 mg, yield: 92%).

Step D: Preparation of Compound 59-5: To a solution of 59-4 (486 mg, 2mmol) and Et₃N (404 mg, 4 mmol) in CH₂Cl₂ (20 mL) was added MsCl (344mg, 3 mmol) at 0° C. The reaction was stirred at room temperature for 1h. TLC showed the reaction was complete. The combined organic layer waswashed with H₂O and brine, dried over sodium sulfate and concentrated invacuo to afford 500 mg of 59-5 as a white solid (yield: 78%).

Step E: Preparation of Compound 59-6: A mixture of 59-5 (500 mg, 1.56mmol), Cs₂CO₃ (846 mg, 2.33 mmol), and5-formyl-4-methyl-1H-indole-2-carbonitrile (143 mg, 0.78 mmol) was mixedin DMF (20 mL). The reaction mixture was heated at 85° C. for 3 h. EtOAc(200 mL) was added into the resulting mixture. The combined organiclayer was washed with H₂O and brine, dried over sodium sulfate andconcentrated. The residue was purified by flash column (eluted 30% EtOAcin pet. ether) to afford 278 mg of 59-6 as a white solid (yield: 43%).

Step F: Preparation of Compound 59-7: A mixture of 59-6 (278 mg, 0.68mmol),N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine(280 mg, 0.88 mmol) and Et₃N (412 mg, 4.08 mmol) in CH₂Cl₂ (20 mL) wasstirred at room temperature for 1 hour. NaBH(OAc)₃ (865 mg, 4.08 mmol)was added to the reaction under ice bath and the reaction mixturestirred at room temperature overnight. The solvent was removed by vacuumand the residue was purified by silica gel column chromatography (eluted2.5% MeOH in dichloromethane) to give 59-7 as a white solid (400 mg,yield: 82%).

Step G: Preparation of Compound 59-8: A solution of 59-7 (200 mg, 0.28mmol) in TFA (15 mL) was stirred at room temperature for 2 hours.Solvent was removed and a solution of NH₃ (7N) in MeOH (10 mL) wasadded. The resulting mixture was concentrated and the residue waspurified by silica gel column chromatography (eluted 10% MeOH indichloromethane) to give 59-8 as an oil (164 mg, yield: 96%).

Step H: Preparation of Compound 59: To a solution of 59-8 (127 mg, 0.21mmol) and Et₃N (43mg, 0.42 mmol) in CH₂Cl₂ (20 mL) was added MsCl (29mg, 0.25 mmol) at 0° C. The reaction was stirred at room temperature for1 h. TLC showed the reaction was complete. The combined organic layerwas washed with H₂O and brine, dried over sodium sulfate, andconcentrated in vacuo to afford 45 mg of 59 as a white solid (yield:31%). ¹HNMR (400 MHz, DMSO) δ: 8.33(s, 1H), 7.87(s, 1H),7.67(s, 1H)7.45-7.56 (m, 3H), 4.35-4.32 (m, 2H), 4.08-4.02 (m, 4H), 3.57-3.54 (m,3H), 3.17(m,1H, 2.88-2.83(m, 6H), 2.54 (s, 3H), 2,20-1.47 (m, 12H), 1.25(d, 3H). ESI-MS m/z: 688.84 (M+H).

Example 2: Synthesis of Compound 48 in Table 1.

Step A: Preparation of Compound 48-2: A mixture of 48-1 (300 mg, 1.40mmol), 2-bromoethanol (347 mg, 2.80 mmol) and K₂CO₃ (772 mg, 5.60 mmol)in CH₃CN (30 mL) was stirred at 90° C. under N₂ overnight. TLC showedthe reaction was complete. Solid was removed by filtration and solventwas removed under vacuum. The residue was purified by silica gel columnchromatography (eluted 2.5% MeOH in dichloromethane) to give 48-2 as ayellow oil (296 mg, yield: 82%).

Step B: Preparation of Compound 48-3: To a mixture of 48-2 (296 mg, 1.15mmol) and Et₃N (232 mg, 2.30 mmol) in dichloromethane (20 mL) was addedMsCl (197 mg, 1.73 mmol) at 0° C. The reaction mixture was stirred atroom temperature for 1 h. TLC showed the reaction was complete.Saturated aqueous NaHCO₃ was added to the reaction mixture. The organiclayer was separated, washed with brine, dried over anhydrous Na₂SO₄, andconcentrated. The residue was purified by silica gel columnchromatography (eluted petroleum) to give 48-3 as an oil (270 mg, yield:70%).

Step C: Preparation of Compound 48-4: A mixture of 48-3 (270 mg, 0.8mmol), 5-formyl-4-methyl-1H-indole-2-carbonitrile (123 mg, 0.67 mmol)and Cs₂CO₃ (524 mg, 1.6 mmol) in DMF (10 mL) was stirred at 80° C. underN₂ overnight. Solid was removed by filtration before the reactionmixture was diluted with water and ethyl acetate. The organic layer wasseparated, washed with brine, dried over anhydrous Na₂SO₄, concentratedand purified by silica gel column chromatography (eluted 20% ethylacetate in petroleum) to give 48-4 as an oil (169 mg, yield: 50%).ESI-MS m/z: 424.54 (M+H).

Step D: Preparation of Compound 48-5: A mixture of 48-4 (169 mg, 0 4mmol),N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine(190 mg, 0.6 mmol) and Et₃N (242 mg, 2.4 mmol) in CH₂Cl₂ (20 mL) wasstirred at room temperature for 1 hour. NaBH(OAc)₃ (508 mg, 2 4 mmol)was added to the reaction under ice bath cooling and the mixturereaction was stirred at room temperature overnight. Solvent was removedby vacuum and the residue was purified by silica gel columnchromatography (eluted 2.5% MeOH in dichloromethane) to give 48-5 as anoil (174 mg, yield: 60%). ESI-MS m/z: 724.88 (M+H).

Step E: Preparation of Compound 48-6: To a solution of 48-5 (174 mg,0.24 mmol) in CH₂Cl₂ (15 mL) was added TFA (5 mL). The reaction wasstirred at room temperature for 2 hours before solvent was removed. Asolution of NH₃/MeOH (7N, 10 mL) was added and the resulting mixture wasconcentrated. The residue and purified by silica gel columnchromatography (eluted 10% MeOH in dichloromethane) to give 48-6 as anoil (120 mg, yield: 80%). ESI-MS m/z: 624.30(M+H).

Step F: Preparation of Compound 48: To a mixture of 48-6 (120 mg, 0.192mmol) and Et₃N (39 mg, 0.384 mmol) in CH₂Cl₂ (10 mL) was added slowlymethanesulfonyl chloride (33 mg, 0.288 mmol) in CH₂Cl₂ (5 mL) at −20° C.under N₂. The reaction mixture was stirred at room temperature for 2hours. TLC showed the reaction was complete. Saturated aqueous NaHCO₃was added to the reaction mixture. The organic layer was separated,washed with brine, dried over anhydrous Na₂SO₄, concentrated andpurified by silica gel column chromatography (eluted 10% MeOH indichloromethane) to give final product 48 as a solid (54 mg, yield:40%). ¹HNMR (400 MHz, CDCl₃) δ: 8.48(s, 1H), 7.38(d, 1H), 7.21(s,1H),7.15(d,1H), 7.08(s,1H), 5.10(d,1H), 4.34(m,2H), 4.24(m,1H),3.87(m, 2H),3.65(m, 4H), 2.93(m, 5H),2.71(m, 2H), 2.63(m, 2H), 2.57(s,3H),2.29(m,2H) , 2.21(m, 2H) ,2.10(d, 2H), 1.61(m, 2H), 1.31(d, 6H); ESI-MS m/z:702.27 (M+H).

Example 3: Synthesis of Compound 2 in Table 1.

Step A: Preparation of Compound 2-2: To a suspension of K₂CO₃ (3.6 g,26.5 mmol) and tert-butyl piperazine-1-carboxylate (1.0 g, 5 3 mmol) inCH₃CN (15 mL) was added methyl 2-bromopropanoate (2.2 g, 13.4 mmol). Thereaction was stirred at 80° C. for 10 hours. TLC showed that thereaction was complete. The reaction mixture was allowed to cool to roomtemperature, then the solid filtered off and solvent removed undervacuum. The residue was purified by silica gel column chromatography(CH₂Cl₂/MeOH=50:1) to give tert-butyl4-(1-methoxy-1-oxopropan-2-yl)piperazine-1-carboxylate (2-2) as a brownoil (1.4 g, yield: 99%).

Step B: Preparation of Compound 2-3: To a solution of tert-butyl4-(1-methoxy-1-oxopropan-2-yl)piperazine-1-carboxylate (540 mg, 2 mmol)in THF (10 mL) was added LiAlH₄ (1.0 mL, 2.5 mol in THF) at 0° C.dropwise. The reaction mixture was stirred at the same temperature for 2hours. TLC showed that the reaction was complete. The reaction wasquenched with EtOAc. The reaction was partitioned between EtOAc and H2O,and the organic layer was washed with brine and dried over Na₂SO₄Solvent was removed under vacuum and the residue was purified by silicagel column chromatography (CH₂Cl₂/MeOH=20:1) to give tert-butyl4-(1-hydroxypropan-2-yl)piperazine-1-carboxylate (2-3) as a brown oil(300 mg, yield: 65%).

Step C: Preparation of Compound 2-5: To a solution of tert-butyl4-(1-hydroxypropan-2-yl)piperazine-1-carboxylate (200 mg, 0.82 mmol) andEt₃N (171 mg, 1.64 mmol) in CH₂Cl₂ (10 mL) was added MsCl (112 mg, 0.98mmol) at 0° C. The reaction was stirred at room temperature for 30 min.The reaction was quenched with NaHCO₃, washed with brine and dried overNa₂SO₄Solvent was removed under vacuum to give tert-butyl4-(1-((methylsulfonypoxy)propan-2-yppiperazine-1-carboxylate (2-4), usedin the next step without further purification.

To a mixture of Cs₂CO₃ (682 mg, 2.1 mmol) and5-formyl-4-methyl-1H-indole-2-carbonitrile (77 mg, 0.42 mmol) in DMF wasadded tert-butyl4-(1-((methylsulfonyl)oxy)propan-2-yl)piperazine-1-carboxylate in DMF.The reaction was stirred at 100° C. for 10 hours. The reaction mixturewas partitioned between EtOAc and H₂O, and the organic layer was washedwith brine and dried over Na₂SO₄. Solvent was removed under vacuum andthe residue was purified by silica gel column chromatography (pet.ether/EtOAc=5:1˜3:1) to give tert-butyl4-(1-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl)propan-2-yl)piperazine-1-carboxylate(2-5) as a yellow solid (90 mg, yield: 53%).

Step D: Preparation of Compound 2-6: A mixture of tert-butyl4-(1-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl)propan-2-yl)piperazine-1-carboxylate(90 mg, 0.22 mmol),6-(2,2,2-trifluoroethyl)-N-(piperidin-4-yl)thieno-[2,3-d]pyrimidin-4-amine(100 mg, 0.26 mmol) and Et₃N (130 mg, 1.32 mmol) in CH₂Cl₂ (10 mL) wasstirred at room temperature for 1 hour before NaBH(OAc)₃ (280 mg, 1.32mmol) was added. The reaction mixture was stirred at room temperatureovernight, then partitioned between CH-2Cl₂ and NaHCO₃. The organiclayer was washed with brine and dried over Na₂SO₄Solvent was removedunder vacuum and the residue was purified by silica gel columnchromatography (CH₂Cl₂:MeOH=50:1˜20:1) to give tert-butyl4-(1-(2-cyano-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)propan-2-yl)piperazine-1-carboxylate(2-6) as a yellow solid (130 mg, yield: 81%).

Step E: Preparation of Compound 2-7: To a solution of tert-butyl4-(2-(2-cyano-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)-1-hydroxyethyl)piperidine-1-carboxylate(130 mg, 0.21 mmol) in CH₂Cl₂ (3 mL) was added TFA (2 mL). The reactionwas stirred for 4 hours before solvent was removed under vacuum. Theresidue was diluted with CH₂Cl₂ and washed with NaHCO₃. The organiclayer was washed with brine and dried over Na₂SO₄Solvent was removedunder vacuum and the residue (2-7) was used without further purificationas a yellow foam (100 mg, yield: 98%).

Step F: Preparation of Compound 2: To a solution of4-methyl-1-(2-(piperazin-1-yppropyl)-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile(60 mg, 0.1 mmol) and Et₃N (36 mg, 0.4 mmol) in CH₂Cl₂ (10 mL) was addedMsCl (21 mg, 0.2 mmol) at 0° C. The reaction was stirred at roomtemperature for 30 min. The reaction was quenched by NaHCO₃, washed withbrine and dried over Na₂SO₄. Solvent was removed and the residue waspurified by Prep-TLC (CH₂Cl₂:MeOH=15:1) to give4-methyl-1-(2-(4-(methylsulfonyppiperazin-1-yppropyl)-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile(compound 2) as a white solid (10 mg, yield: 20%). 41 NMR (400 MHz,CDCl₃) 8.48(s, 1H), 7.36(d, 1H), 7.20(s, 1H), 7.00-7.15(m, 2H), 5.16 (d,1H), 4.20-4.40(m, 2H), 4.00-4.10(m, 1H), 3.60- 3.70 (m,4H), 3.10-3.30(m,5H), 2.80-2.90 (m, 4H), 2.77 (s, 3H), 2.57 (s, 3H), 1.56-2.53(m, 8H),1.08 (d,3H).

ESI-MS m/z: 689.25 (M+H).

Example 4: Synthesis of Compound 61 in Table 1.

Step A: Preparation of Compound 61-2: A mixture of ethyl1-aminocyclopropanecarboxylate hydrochloride (2.4 g, 14.5 mmol),N-benzyl-2-chloro-N-(2-chloroethyl)ethanamine hydrochloride (4.26 g, 158 mmol), and N,N-Diisopropylethylamine (25 mL) in ethanol (32 mL) wasstirred at reflux for 16 hours. The reaction mixture was concentrated todryness. The residue was partitioned between dichloromethane and water.Two layers were separated, and the aqueous layer was extracted withdichloromethane. The combined organic layers were concentrated. Theresidue was purified by silica gel column (pet. ether/EtOAc=1:0-10:1) togive ethyl 1-(4-benzylpiperazin-1-yl)cyclopropanecarboxylate (61-2, 1.8g, yield: 43%) as a yellow oil. ¹1-1NMR (400 MHz, CDCl₃) δ: 7.37-7.27(m, 5H), 4.19-4.13 (m, 2H), 3.54 (s, 2H), 3.00(brs, 2H), 2.39 (brs, 2H),1.31-1.26 (m, 5H), 7.52 (m 1H), 0.93-0.91 (m, 2H).

Step B: Preparation of Compound 61-3: To a mixture of ethyl1-(4-benzylpiperazin-1-yl)cyclopropanecarboxylate (880 mg, 3 mmol) inTHF (12 mL) was added LiAlH₄ (290 mg, 6 mmol) slowly at 0° C. Theresulting mixture was stirred at 0° C. for 1 h. Water (0.5 mL) wasadded, followed by ethyl acetate (20 mL). Solid was filtered off andsolvent was removed. The residue was purified by silica gel column (pet.ether/EtOAc=3:1) to give (1-(4-benzylpiperazin-1-yl)cyclopropyl)methanol(61-3, 660 mg, yield: 88%) as a white solid.

Step C: Preparation of Compound 61-4: A mixture of(1-(4-benzylpiperazin-1-yl)cyclopropyl)methanol (600 mg, 2 4 mmol) andPd/C (10%, 50 mg) in ethanol (10 mL) was stirred at 50° C. overnightunder H2. The reaction mixture was filtered and the filtrateconcentrated to give (1-(piperazin-1-yl)cyclopropyl)methanol (61-4) asan oil (400 mg, yield: 96%). The crude product was used in the next stepwithout further purification.

Step D: Preparation of Compound 61-5: To a mixture of(1-(piperazin-1-ypcyclopropyl)methanol (400 mg, 2.5 mmol) indichloromethane (10 mL) was added Et₃N (1.1 mL, 7.5 mmol), followed by amixture of methanesulfonyl chloride (925 mg, 7.5 mmol) indichloromethane (5 mL). The resulting mixture was stirred at roomtemperature for 4 h. The reaction mixture was diluted with water andCH₂Cl₂. The organic layer was dried over Na₂SO₄, and concentrated togive a crude product(1-(4-(methylsulfonyl)piperazin-1-yl)cyclopropyl)methyl methanesulfonate(61-5) as a brown oil (500 mg).

Step E: Preparation of Compound 61-6: A mixture of crude(1-(4-(methylsulfonyl)piperazin-1-yl)cyclopropyl)methyl methanesulfonate(500 mg), 5-formyl-4-methyl-1H-indole-2-carbonitrile (200 mg, 1.1 mmol),and K₂CO₃ (800 mg, 5.8 mmol) in acetonitrile was stirred at 80° C.overnight. The mixture was filtered and the filtrate was concentrated todryness. The residue was purified by silica gel column (pet.ether/EtOAc=3:1) to give5-formyl-4-methyl-1-((1-(4-(methylsulfonyl)piperazin-1-yl)cyclopropyl)methyl)-1H-indole-2-carbonitrile(61-6, 330 mg) as a brown solid. ESI-MS m/z: 401 (M+H).

Step F: Preparation of Compound 61: A mixture of5-formyl-4-methyl-1-((1-(4-(methylsulfonyppiperazin-1-ypcyclopropyl)methyl)-1H-indole-2-carbonitrile(330 mg, crude),N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-aminehydrochloride (391 mg, 1.1 mmol), and Et₃N (0.5 mL) in dichloromethane(12 mL) was stirred at room temperature overnight. The reaction mixturewas diluted with water and CH₂Cl₂. The organic layer was separated,dried over Na₂SO₄, and concentrated. The residue was purified by silicagel column (dichloromethane/methanol=50:1-30:1) to give a crude product.The crude product was purified by Prep-TLC with dichloromethane/methanol(7N NH₃/MeOH)=50:1 to give the product (compound 61) as a colorlesssolid (12 mg). ESI-MS m/z: 701 (M+H). ¹H-NMR (400 MHz, CDCl₃) 6: 8.46(s, 1H), 7.20-7.28 (m, 3H), 4.30-4.36 (m, 3H), 3.84 (brs, 2H), 3.61-3.68(m, 2H), 3.09-3.13 (m, 6H), 2.76 (s, 3H), 2.64-2.66 (m, 4H), 2.59 (s,3H), 2.40-2.48 (m, 2H), 2.14-2.18 (m, 2H), 1.87-1.90 (m, 2H), 0.79-0.82(t, 2H), 0.61-0.64 (t, 2H).

Example 5: Synthesis of Compound 35 in Table 1.

Step A: Preparation of Compound 35-2: A mixture of tert-butylpiperazine-1-carboxylate (1.9 g, 10 mmol) and Et₃N (3 g, 30 mmol) inCH₂Cl₂ (40 mL) was stirred at 0° C. before 2-chloroacetyl chloride (2.2g, 20 mmol) was added slowly. The reaction mixture was stirred at 0° C.under N2 for 4 hr. TLC showed that the reaction was complete. Thereaction mixture was partitioned between CH₂Cl₂ and H₂O, and the organiclayer was washed with brine and dried over Na₂SO₄Solvent was removedunder vacuum and the residue (35-2) was used without furtherpurifications as light yellow oil (2.5 g, yield: 95%).

Step B: Preparation of Compound 35-3: To a mixture ofN-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-amine(1 g, 4 mmol), and 5-formyl-4-methyl-1H-indole-2-carbonitrile (540 mg, 3mmol) in THF (10 mL) was added NaH (180 mg, 4.5 mmol) at 0° C. Thereaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was then partitioned between EtOAc and H₂O, and theorganic layer was washed with brine and dried over Na₂SO₄Solvent wasremoved under vacuum and the residue purified by silica gel columnchromatography (pet. ether:EtOAc=10:1˜1:1) to give tert-butyl4-(2-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl)acetyl)piperazine-1-carboxylate(35-3) as a light yellow solid (60 mg, yield: 4%).

Step C: Preparation of Compound 35-4: A mixture of methyl tert-butyl4-(2-(2-cyano-5-formyl-4-methyl-1H-indol-1-yl)acetyl)piperazine-1-carboxylate(40 mg, 0.1 mmol),N-(piperidin-4-yl)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-aminehydrochloride (60 mg, 0.2 mmol) and Et₃N (60 mg, 0.6 mmol) in CH₂Cl₂ (5mL) was stirred at room temperature for 2 hours. NaBH(OAc)₃ (120 mg, 0 6mmol) was then added to the reaction with ice bath cooling. The reactionmixture was stirred at room temperature overnight. The reaction waspartitioned between CH₂Cl₂ and NaHCO₃, and the organic layer was washedwith brine and dried over Na₂SO₄. Solvent was removed under vacuum andthe residue was purified by silica gel column chromatography(CH₂Cl₂:MeOH=100:1-20:1) to give tert-butyl4-(2-(2-cyano-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)acetyppiperazine-1-carboxylate(35-4) as a yellow solid (40 mg, yield: 55%).

Step D: Preparation of Compound 35-5: A solution of tert-butyl4-(2-(2-cyano-4-methyl-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)acetyl)piperazine-1-carboxylate(40 mg, 0.06 mmol) in HCl MeOH (10 mL) was stirred at room temperaturefor 16 h. TLC showed that the reaction was complete. Solvent was removedunder vacuum and the residue (35-5) was used without furtherpurification in next step as a yellow solid (35 mg, yield: 85%).

Step E: Preparation of Compound 35: To a mixture of4-methyl-1-(2-oxo-2-(piperazin-1-yl)ethyl)-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile(35mg, 0.05 mmol) and Et₃N (15 mg, 0.15 mmol) in CH₂Cl₂ (10 mL) was slowlyadded MsCl(12 mg, 0.1 mmol) at 0° C. The reaction mixture was stirred atroom temperature for 4 hours and then partitioned between CH₂Cl₂ andNaHCO₃. The organic layer was washed with brine and dried over Na₂SO₄.Solvent was removed under vacuum and the residue was purified byPrep-TLC (CH₂Cl₂:MeOH=20:1) to give4-methyl-1-(2-(4-(methylsulfonyl)piperazin-1-yl)-2-oxoethyl)-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile(compound 35) as a white solid (16 mg, yield: 56%). ¹HNMR (400 MHz,CDCl₃) 8.42 (s, 1H), 7.84˜7.76 (m,1H), 7.33˜7.22 (m,3H), 5.15 (s, 2H),4.37˜4.08(m, 2H), 3.78(s, 3H), 3.69˜3.61(m, 2H), 3.44˜3.30(m, 5H),2.86(s, 3H), 2.70˜2.54 (m, 4H), 2.15˜2.06 (m, 3H), 1.35˜1.23 (m, 4H),0.91·0.85 (m, 2H).

Example 6: Fluorescence polarization assay. This example illustrates anassay effective in monitoring the binding of MLL to menin. Fluorescencepolarization (FP) competition experiments were performed to determinethe effectiveness with which a compound inhibits the menin-MLLinteraction, reported as an IC₅₀ value. A fluorescein-labeled peptidecontaining the high affinity menin binding motif found in MLL wasproduced according to Yokoyama et al. (Cell, 2005, 123(2): 207-218),herein incorporated by reference in its entirety. Binding of the labeledpeptide (1.7 kDa) to the much larger menin (˜67 kDa) is accompanied by asignificant change in the rotational correlation time of thefluorophore, resulting in a substantial increase in the fluorescencepolarization and fluorescence anisotropy (excitation at 500 nm, emissionat 525 nm). The effectiveness with which a compound inhibits themenin-MLL interaction was measured in an FP competition experiment,wherein a decrease in fluorescence anisotropy correlates with inhibitionof the interaction and was used as a read-out for IC₅₀ determination.

Table 3 shows biological activities of selected compounds in afluorescence polarization assay. Compound numbers correspond to thenumbers and structures provided in Tables 1 and 2 and Examples 1-5.

TABLE 3 Less than 50 nM to less than 20 nM to Greater than 50 nM (++++)250 nM (+++) 1000 nM (++) 1000 nM (+) Menin 6, 8, 10, 12, 13, 14, 2, 4,5, 7, 11, 17, 1, 3, 24, 26, 44, 45, 9, 15, 16, 23, 35, MLL 4-43 18, 20,22, 27, 28, 19, 21, 25, 29, 30, 52, 53, 55, 56, 57, 47, 60, 62, 71, 170,IC₅₀ (nM) 64, 65, 73, 80, 85, 43, 46, 48, 49, 54, 58, 59, 66, 67, 82,200, 242, 252, 88, 89, 90, 92, 93, 61, 68, 69, 70, 72, 118, 157, 169,173, 1010, 1012 115, 119, 123, 129, 74, 84, 87, 91, 94, 201, 1000, 1001,131, 132, 134, 135, 116, 117, 120, 121, 1011 136, 138, 139, 141, 122,124, 125, 126, 147, 148, 149, 151, 127, 128, 130, 133, 154, 158, 163,165, 137, 140, 142, 143, 166, 172, 175, 176, 144, 145, 146, 150, 177,178, 181, 182, 152, 153, 155, 156, 183, 184, 186, 187, 159, 160, 161,162, 189, 191, 192, 193, 164, 167, 168, 171, 194, 196, 197, 202, 174,179, 180, 185, 203, 204, 205, 206, 188, 190, 195, 198, 207, 209, 210,212, 199, 208, 211, 230, 213, 214, 215, 216, 241, 245, 280, 217, 219,220, 221, 1002, 1003, 1013, 222, 225, 226, 229, 1023 233, 239, 243, 244,246, 247, 248, 249, 250, 251, 281, 282, 283, 1020, 1021, 1022, 1024,1025, 1026, 1027

Example 7: Homogenous time-resolve fluorescence (HTRF) assay. Ahomogeneous time-resolve fluorescence (HTRF) assay is utilized as asecondary assay to confirm the results of the FP assay. In someembodiments, the HTRF assay is the primary assay and the FP assay isused as a secondary assay to confirm results. HTRF is based on thenon-radiative energy transfer of the long-lived emission from theEuropium cryptate (Eu³⁺-cryptate) donor to the allophycocyanin (XL665)acceptor, combined with time-resolved detection. An Eu³⁺-cryptate donoris conjugated with mouse anti-6His monoclonal antibody (which bindsHis-tagged menin) and XL665-acceptor is conjugate to streptavidin (whichbinds biotinylated MLL peptide). When these two fluorophores are broughttogether by the interaction of menin with the MLL peptide, energytransfer to the acceptor results in an increase in fluorescence emissionat 665 nm and increased HTRF ratio (emission intensity at 665nm/emission intensity at 620 nm). Inhibition of the menin-MLLinteraction separates the donor from the acceptor, resulting in adecrease in emission at 665 nm and decreased HTRF ratio.

Example 8: Menin engagement assay. Sample Preparation: 2.5 μl of 100 μMcompound is added to 47.5 μl of 526 nM menin in PBS (5 μM compound 500nM menin in 5% DMSO final concentration). The reaction is incubated atroom temperature for variable lengths of time and quenched with 2.5 μlof 4% formic acid (FA, 0.2% final concentration). Method: A ThermoFinnigan Surveyor Autosampler, PDA Plus UV detector and MS Pump alongwith an LTQ linear ion trap mass spectrometer were used to collectsample data under XCalibur software control. A 50 μl, sample in “nowaste” mode was injected onto a Phenomenex Jupiter 5u 300A C5 (guardcolumn) 2×4.00 mm at 45° C. Mobile phase composition: Buffer A (95:5water:acetonitrile, 0.1% FA) and Buffer B (acetonitrile, 0.1% FA).Gradient elution was used with an initial mobile phase of 85:15 (BufferA:B) and a flow rate of 250 μL/min. Upon injection, 85:15 A:B was heldfor 1.3 min, Buffer B was increased to 90% over 3.2 min, held for 1 min,and then returned to initial conditions in 0.1 min and held for 2.4 min.The total run time is 8 min. A post-column divert valve employed todirect void volume salts to waste was used for the first 2 min of thesample method. Blank injection of Buffer A is used in between each ofthe sample injections. A needle wash of 1:1 acetonitrile:water with 0.1%FA was used. The electrospray ionization (ESI) source used a 300° C.capillary temperature, 40 units sheath gas flow, 20 units aux gas flow,3 units sweep gas flow, 3.5 kV spray voltage, 120 V tube lens. DataCollection: Data collection was performed in the positive ion full scanmode 550-1500 Da, 10 microscans, 200 ms max ion time. Data analysis:Protein mass spectra were acquired as XCalibur datafiles. The best scanswere added together using XCalibur Qual Browser. The spectra weredisplayed using View/Spectrum List with a Display option to display allpeaks. The Edit/Copy cell menu was used to copy the mass spectrum intothe PC clipboard. The spectrum in the PC clipboard was pasted intoExcel. The first two columns (m/z and Intensity were kept and the thirdcolumn (Relative) was deleted. The remaining two columns were then savedas a tab delimited file (m/z and intensity) as filename.txt from Excel.The Masslynx Databridge program was then used to convert thefilename.txt tab delimited file to Masslynx format. In some cases, anexternal calibration using a (similarly converted) myoglobin spectrumwas applied in Masslynx to correct the m/z values of the menin proteinm/z data. MaxEntl software from the MassLynx software suite was used fordeconvolution of the mass spectrum to yield the average MW of theprotein(s). The percentage of covalent adduct formation was determinedfrom the deconvoluted spectrum and used to calculate the reaction rate(k) of the covalent reaction.

Example 9: Cell proliferation assay. The ability of a compound of thepresent disclosure to inhibit the growth of cells, such as humanleukemia cell, acute myeloid leukemia cell, cells with an MLL fusion,control cells without an MLL fusion, VCaP, LNCaP, 22RV1, DU145,LNCaP-AR, MV4;11, KOPN-8, ML-2, MOLM-13, RS4;11, SEM, bone marrow cells(BMCs), MLL-AF9, MLL-AF4, MLL-ENL, MLL-CBP, MLL-GAS7, MLL-AF1p, MLL-AF6,HM-2, E2A-HLF, REH, U937, K562, KG-1, HL-60 and NB4 cells, is testedusing a cell viability assay, such as the Promega CellTiter-Glo®Luminescent Cell Viability Assay (Promega Technical Bulletin, 2015,“CellTiter-Glo® Luminescent Cell Viability Assay”: 1-15, hereinincorporated by reference in its entirety). Cells are plated at relevantconcentrations, for example about 1×10⁵-2×10⁵ cells per well in a96-well plate. A compound of the present disclosure is added at aconcentration up to about 2 μM with eight, 2-fold serial dilutions foreach compound. Cells are incubated at 37° C. for a period of time, forexample, 72 hours, then cells in the control wells are counted. Media ischanged to restore viable cell numbers to the original concentration,and compounds are re-supplied. Proliferation is measured about 72 hourslater using Promega CellTiter-Glo® reagents, as per kit instructions.Certain compounds disclosed herein exhibited GI₅₀ values of less than250 nM or less than 50 nM when tested in MV4;11 cells. As used in theExamples, the GI₅₀ value of a compound is the concentration of thecompound for 50% of maximal inhibition of cell proliferation.

Table 4 shows biological activities of selected compounds in a cellproliferation assay. Compound numbers correspond to the numbers andstructures provided in Tables 1 and 2 and Examples 1-5

TABLE 4 Less than 10 nM to 50 nM 250 nM 10 nM less than to 250 to 1000(++++) 50 nM (+++) nM (++) nM (+) MLL-AF9 132, 135, 151, 163, 10, 80,138, 139, 9 BMC GI₅₀ 165, 172, 177, 183, 171, 174, 175, (nM) 199, 203,205, 207, 176, 181, 217 214

Example 10: RT-PCR analysis ofMLL fusion protein downstream targets. Theeffect of a compound of the present disclosure on expression of one ormore MLL fusion protein downstream targets is assessed by RT-PCR. Cells,such as human leukemia cell, acute myeloid leukemia cell, cells with anMLL fusion, control cells without an MLL fusion, VCaP, LNCaP, 22RV1,DU145, LNCaP-AR, MV4;11, KOPN-8, ML-2, MOLM-13, RS4;11, SEM, bone marrowcells (BMCs), MLL-AF9, MLL-AF4, MLL-ENL, MLL-CBP, MLL-GAS7, MLL-AF1p,MLL-AF6, HM-2, E2A-HLF, REH, U937, K562, KG-1, HL-60 and NB4 cells, aretreated with an effective concentration of a compound disclosed hereinfor about 7 days or less, then total RNA is extracted from cells usingany available kit such as an RNeasy mini kit (QIAGEN) according to themanufacturer's instructions. Total RNA is reverse transcribed using aHigh Capacity cDNA Reverse Transcription Kit (Applied Biosystems), andrelative quantification of relevant gene transcripts (e.g., Hoxa9, DLX2,and Meis1) is determined by real-time PCR. Effective inhibition of themenin-MLL interaction is expected to result in the downregulation ofdownstream targets of MLL, including Hoxa9, DLX2, and Meis1 .

Example 11: Pharmacokinetic studies in mice. The pharmacokinetics ofmenin-MLL inhibitors are determined in female C57BL/6 mice followingintravenous (iv) dosing at 15 mg/kg and oral dosing (po) at 30 mg/kg.Compounds are dissolved in the vehicle containing 25% (v/v) DMSO, 25%(v/v) PEG-400 and 50% (v/v) PBS. Serial blood samples (50 μL) arecollected over 24 h, centrifuged at 15,000 rpm for 10 min and saved foranalysis. Plasma concentrations of the compounds are determined by theLC-MS/MS method developed and validated for this study. The LC-MS/MSmethod consists of an Agilent 1200 HPLC system and chromatographicseparation of tested compound is achieved using an Agilent ZorbaxExtend-C18 column (5 cm×2.1 mm, 3.5 μm; Waters). An AB Sciex QTrap 3200mass spectrometer equipped with an electrospray ionization source(ABI-Sciex, Toronto, Canada) in the positive-ion multiple reactionmonitoring (MRM) mode is used for detection. All pharmacokineticparameters are calculated by noncompartmental methods using WinNonlin®version 3.2 (Pharsight Corporation, Mountain View, Calif., USA).

Example 12: Efficacy study in mouse xenograft tumor modelImmunodeficient mice, such as 8-10 week-old female nude (nu/nu) mice,are used for in vivo efficacy studies in accordance with the guidelinesapproved by IACUC. Leukemia cells, such as human MV4-11 leukemia cellsavailable from ATCC, are implanted subcutaneously via needle into femalenude mice (5×10⁶ cells/mouse). When the tumor reaches a size ofapproximately 150 to 250 mm³ in mice, the tumor-bearing mice arerandomly assigned to a vehicle control or compound treatment group (8animals per group) Animals are treated with a compound of the presentdisclosure by oral gavage or intraperitoneal injection in an appropriateamount and frequency as can be determined by the skilled artisan withoutundue experimentation. Subcutaneous tumor volume in nude mice and micebody weight are measured twice weekly. Tumor volumes are calculated bymeasuring two perpendicular diameters with calipers(V=(length×width²)/2). Percentage tumor growth inhibition (%TGI=1[change of tumor volume in treatment group/change of tumor volumein control group]*100) is used to evaluate anti-tumor efficacy.Statistical significance is evaluated using a one-tailed, two sample ttest. P<0.05 is considered statistically significant.

Example 13: Efficacy study in prostate tumor xenograft modelImmunodeficient mice, such as 4-6 week-old male CB17 severe combinedimmunodeficiency (SCID) mice, are used for in vivo efficacy studies inaccordance with the guidelines approved by IACUC. Parental prostatecancer cells, such as VCaP or LNCaP-AR cells, are implantedsubcutaneously into male CB.17.SCID mice (3-4×10⁶ cells in 50%Matrigel). When the tumor reaches a palpable size of approximately 80mm³, the tumor-bearing mice are randomly assigned to a vehicle controlor compound treatment group (6 or more animals per group). Animals aretreated with a compound of the present disclosure by intraperitonealinjection in an appropriate amount and frequency as can be determined bythe skilled artisan without undue experimentation. In one example, miceare treated with 40 mg/kg of a compound of the present disclosure dailyby i.p. injection for two weeks, then 5 days per week thereafter.Subcutaneous tumor volume and mice body weight are measured twiceweekly. Tumor volumes are calculated by measuring two perpendiculardiameters with calipers (V=(length×width²)/2).

Example 14: Efficacy study in castration-resistant prostate tumorxenograft model (VCaP). Immunodeficient mice, such as 4-6 week-old maleCB17 severe combined immunodeficiency (SCID) mice, are used for in vivoefficacy studies in accordance with the guidelines approved by IACUC.Parental prostate cancer cells, such as VCaP cells, are implantedsubcutaneously into male CB.17.SCID mice (3-4×10⁶ cells in 50%Matrigel). When the tumor reaches a size of approximately 200-300 mm³,the tumor-bearing mice are physically castrated and tumors observed forregression and regrowth to approximately 150 mm³ The tumor-bearing miceare randomly assigned to a vehicle control or compound treatment group(6 or more animals per group) Animals are treated with a compound of thepresent disclosure by intraperitoneal injection in an appropriate amountand frequency as can be determined by the skilled artisan without undueexperimentation. In one example, mice are treated with 40 mg/kg of acompound of the present disclosure daily by i.p. injection. Subcutaneoustumor volume and mice body weight are measured twice weekly. Tumorvolumes are calculated by measuring two perpendicular diameters withcalipers (V=(length×width²)/2).

Example 15: Efficacy study in castration-resistant prostate tumorxenograft model (LNCaP-AR). Immunodeficient mice, such as 4-6 week-oldmale CB17 severe combined immunodeficiency (SCID) mice, are used for invivo efficacy studies in accordance with the guidelines approved byIACUC. CB.17.SCID mice are surgically castrated and allowed to recoverfor 2-3 weeks before implanting parental prostate cancer cells, such asLNCaP-AR cells, subcutaneously into (3-4×10⁶ cells in 50% Matrigel).When the tumor reaches a size of approximately 80-100 mm³, thetumor-bearing mice are randomly assigned to a vehicle control orcompound treatment group (6 or more animals per group). Animals aretreated with a compound of the present disclosure by intraperitonealinjection in an appropriate amount and frequency as can be determined bythe skilled artisan without undue experimentation. In one example, miceare treated with 60 mg/kg of a compound of the present disclosure dailyby i.p. injection for 27 days. Subcutaneous tumor volume and mice bodyweight are measured twice weekly. Tumor volumes are calculated bymeasuring two perpendicular diameters with calipers(V=(length×width²)/2).

Example 16: Cellular Thermal Shift Assay (CETSA). For the cell lysateCETSA experiments, cultured cells from cell lines (e.g., HEK293, bonemarrow samples) are harvested and washed with PBS. The cells are dilutedin kinase buffer (KB) (25 mM Tris(hydroxymethyl)- aminomethanehydrochloride (Tris-HCl, pH 7.5), 5 mM beta-glycerophosphate, 2 mMdithiothreitol (DTT), 0.1 mM sodium vanadium oxide, 10 mM magnesiumchloride) or in phosphate-buffered saline (PBS) (10 mM phosphate buffer(pH 7.4), 2.7 mM potassium chloride and 137 mM sodium chloride). Allbuffers are supplemented with Complete protease inhibitor cocktail. Thecell suspensions are freeze-thawed three times using liquid nitrogen.The soluble fraction (lysate) is separated from the cell debris bycentrifugation at 20000×g for 20 minutes at 4° C. The cell lysates arediluted with appropriate buffer and divided into two aliquots, with onealiquot being treated with drug and the other aliquot with the diluentof the inhibitor (control). After 10-30 minute incubation at roomtemperature the respective lysates are divided into smaller (50 μL)aliquots and heated individually at different temperatures for 3 minutesfollowed by cooling for 3 minutes at room temperature. The appropriatetemperatures are determined in preliminary CETSA experiments. The heatedlysates are centrifuged at 20000×g for 20 minutes at 4° C. in order toseparate the soluble fractions from precipitates. The supernatants aretransferred to new microtubes and analyzed by sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS-PAGE) followed by western blotanalysis.

For the intact cell experiments the drug-treated cells from the in vitroexperiments above are heated as previously described followed byaddition of KB (30 μL) and lysed using 2 cycles of freeze-thawing withliquid nitrogen. The soluble fractions are isolated and analyzed bywestern blot.

For the in vivo mice experiments, lysates of frozen tissues are used.The frozen organs (e.g., liver or kidney) are thawed on ice and brieflyrinsed with PBS. The organs are homogenized in cold PBS using tissuegrinders followed by 3 cycles of freeze-thawing using liquid nitrogen.Tissue lysates are separated from the cellular debris and lipids. Thetissue lysates are diluted with PBS containing protease inhibitors,divided into 500 μL aliquots and heated at different temperatures.Soluble fractions are isolated and analyzed by western blot.

It is expected that the aliquots treated with one or more of thecompounds disclosed herein exhibit increased thermal stabilization ofmenin compared to the control aliquots.

Example 17: CETSA-like dot-blot experiments on purified proteins.Purified protein (0.5 g) is added to the wells of a PCR plate and thevolume adjusted to 50 μL by addition of buffer or cell lysates andligands depending on the experimental setup. The samples are heated forthe designated time and temperature in a thermocycler. After heating,the samples are immediately centrifuged for 15 min at 3000×g andfiltered using a 0.65 μm Multiscreen HTS 96 well filter plate. 3 μL ofeach filtrate are blotted onto a nitrocellulose membrane. Primaryantibody and secondary conjugate are used for immunoblotting. Allmembranes are blocked with blocking buffer; standard transfer andwestern blot protocols recommended by the manufacturers are used. Allantibodies are diluted in blocking buffer. The dot-blot is developed.Chemiluminescence intensities are detected and imaged. Raw dot blotimages are processed. The background is subtracted and intensities arequantified. Graphs are plotted and fitted using sigmoidal dose-response(variable slope).

Example 18: Cell proliferation assays. The ability of a compound of thepresent disclosure to inhibit the growth of cells was tested in both MLLleukemia cell lines (e.g., MV4;11, MOLM13 and/or KOPN8) and control celllines (e.g., K562, REH, U937, KG-1, and/or HL-60) using the MTT cellproliferation assay (ATCC® 30-1010K). One or more compounds disclosedherein, e.g., a compound provided in Table 3 having an IC₅₀ value ofless than 1 μM, preferably less than 50 nM (a measurement reflecting theability of the compound to disrupt the menin-MLL interaction, measuredin accordance with Example 6), inhibit the proliferation of MLL leukemiacell lines (MV4;11 and MOLM13 cells) while having a much weakerinhibitory effect on the proliferation of control cell lines (e.g., K562and REH cells) at the same concentration. Cells were plated at about1×10⁵ cells per well in a 96-well plate. A compound of the presentdisclosure was added at a concentration up to about 2 μM with seven,2-fold serial dilutions for each compound. Cells were incubated at 37°C. for 72 hours, then cells in the control wells were counted. Media waschanged to restore viable cell numbers to the original concentration,and compounds were re-supplied. Proliferation was measured 96 hourslater using MTT reagents, as per kit instructions. The GI₅₀ value of acompound of the present disclosure, such as Compound B of FIG. 4, was 35nM in MV4;11 cells (MLL-AF4 AML), 75 nM in MOLM13 cells (MLL-AF9 AML),1500 nM in K562 cells, and 2000 nM in REH cells, as measured by the MTTcell proliferation assay. The GI₅₀ value of a compound of the presentdisclosure, such as Compound C of FIG. 8, was 15 nM in MV4;11 cells(MLL-AF4 AML), 16 nM in MOLM13 cells (MLL-AF9 AML), 20 nM in KOPN8(MLL-ENL AML) cells, 1500 nM in REH cells, greater than 6000 nM in K562cells, and greater than 6000 nM in U937 cells, as measured by the MTTcell proliferation assay. The GIso value of a compound of the presentdisclosure, such as Compound D of FIG. 11, was 10 nM in MV4;11 cells(MLL-AF4 AML), 17 nM in MOLM13 cells (MLL-AF9 AML), 18 nM in KOPN8(MLL-ENL AML) cells, greater than 2000 nM in HL-60 cells, and greaterthan 2000 nM in U937 cells. REH, K562, KG-1, and U937 cells are controlcell lines without MLL fusions. Certain compounds disclosed hereinexhibited GI₅₀ values in the range of 1500 nM to greater than 6000 nMwhen tested in REH, K562, KG-1, and U937 cells. Certain compoundsdisclosed herein exhibited GIso values in the range of 5 nM to 25 nMwhen tested in MV4;11 cells (MLL-AF4 AML), MOLM13 cells (MLL-AF9 AML),murine bone marrow cells (rMML-AF9 AML), KOPN8 (MLL-ENL AML) cells,RS4;11 cells (MLL-AF4 ALL), or SEM (MLL-AF4 ALL) cells.

Example 19: Efficacy study in mouse xenograft tumor model. One or morecompounds disclosed herein, e.g., a compound provided in Table 3 havingan IC₅₀ value of less than 1 μM, preferably less than 50 nM (ameasurement reflecting the ability of the compound to disrupt themenin-MLL interaction, measured in accordance with Example 6), providesuppression of MV4;11 (human leukemia) tumor growth in mouse xenograftmodels Immunocompromised 8-10 week-old female nude (nu/nu) mice wereused for in vivo efficacy studies in accordance with IACUC guidelines.Human MV4;11 leukemia cells available from ATCC were implantedsubcutaneously into female nude mice (5×10⁶ cells/mouse). When the tumorreached a size of approximately 150 to 250 mm³, the tumor-bearing micewere randomly assigned to a vehicle control or a compound treatmentgroup (8 mice per group). Mice in each treatment group were administereda compound of the present disclosure by oral gavage at the dosageindicated (50 mg/kg, bid; 50 gm/kg, qd; 100 mg/kg, bid; 100 mg/kg, qd;200 mg/kg, qd.; or 200 mg/kg, bid). Subcutaneous tumor volume and mousebody weight were measured twice weekly. Tumor volumes were calculated bymeasuring two perpendicular diameters with calipers(V=(length×width)/2). As shown in FIG. 4, a compound provided in Table 3having an IC₅₀ value of less than 50 nM (a measurement reflecting theability of the compound to disrupt the menin-MLL interaction, measuredin accordance with Example 6), labeled Compound B in the figure,inhibited tumor growth and induced tumor regression relative to thevehicle control group in a dose-dependent manner As shown in FIG. 8, acompound provided in Table 3 having an IC₅₀ value of less than 50 nM (ameasurement reflecting the ability of the compound to disrupt themenin-MLL interaction, measured in accordance with Example 6), labeledCompound C in the figure, inhibited tumor growth and induced tumorregression relative to the vehicle control group in a dose-dependentmanner.

Example 20: Efficacy study in xenotransplantation mouse model ofMLLleukemia. One or more compounds disclosed herein, e.g., a compoundprovided in Table 3 having an IC₅₀ value of less than 1 μM, preferablyless than 50 nM (a measurement reflecting the ability of the compound todisrupt the menin-MLL interaction, measured in accordance with Example6), provide suppression of MV4;11 tumor growth in a xenotransplantationmouse model of MLL leukemia Immunocompromised 8-10 week-old female NSGmice were used for in vivo efficacy studies in accordance with IACUCguidelines. Luciferase expressing human MV4;11 leukemia cells(MV4;11-luc) were engrafted intravenously via tail vein injection (1×10⁷cells/animal) When the mean luminescence of the cells reachedapproximately 1.5×10⁶, the tumor-bearing mice were randomly assigned toa vehicle control or a compound treatment group (5 animals per group).Animals in each of the treatment groups were administered a differentcompound of the present disclosure by oral gavage (120 mg/kg b.i.d, 150mg/kg b.i.d., 200 mg/kg b.i.d., or 200 mg/kg q.d.). Body weight wasmeasured daily, while mean luminescence was measured 6 days afterinitiating the treatment with compound or vehicle.

As shown in FIG. 5, a 200 mg/kg b.i.d. treatment regimen of Compound Bof the present disclosure inhibited tumor growth and induced tumorregression relative to the vehicle control group. By contrast, acompound provided in Table 3 having an IC₅₀ value of greater than 1 μM(a measurement reflecting the ability of the compound to disrupt themenin-MLL interaction, measured in accordance with Example 6), labeledCompound A in FIG. 5, inhibited tumor growth but did not induce tumorregression relative to the vehicle control group when administered at200 mg/kg b.i.d. As shown in FIG. 11, a 120 mg/kg b.i.d. treatmentregimen of Compound 165a compound provided in Table 3 having an IC₅₀value of less than 50 nM (a measurement reflecting the ability of thecompound to disrupt the menin-MLL interaction, measured in accordancewith Example 6) and labeled Compound D in the figuresinhibited tumorgrowth and induced tumor regression relative to the vehicle controlgroup.

Animals were sacrificed on Day 7 of treatment and bone marrow samplescollected and prepared for gene expression analysis. Expression levelsof MLL fusion protein target genes HOXA9, DLX2, and/or MEIS1 weremeasured by qRT-PCR and are presented in FIG. 6, FIG. 9 and FIG. 12 asfold changes normalized to GAPDH expression. Expression ofdifferentiation marker CD1 lb was elevated in bone marrow samples fromCompound B-treated animals, Compound C-treated animals and CompoundD-treated animals, suggesting that these cells undergo differentiation.In addition, the expression levels of MEIS1 and HOXA9 were substantiallyreduced upon treatment with Compound B, Compound C or Compound D,consistent with inhibition of leukemia progression induced by thiscompound.

Example 21: Survival study in xenotransplantation mouse model ofMLLleukemia. For survival studies in the xenotransplantation MV4;11xenograft model, 6 to 8-week old female NSG mice were intravenouslyinjected with 1×10⁷ luciferase-expressing MV4;11 cells harboringMLL-A.F4 translocation. At day 12 after transplantation, treatment wasinitiated with Compound B, 120 inizikg, b.i.d., p.o. or vehicle (20%2-hydroxypropyl-b-cyclodextrin with 5% creinophore) and was continuedfor 22 consecutive days. As shown in FIG. 7, Compound B of the presentdisclosure extended median survival time relative to the vehicle controlgroup. Mice treated with Compound B had a median survival time of 54days, while mice in the vehicle control group had a median survival timeof 37 days, indicating a survival benefit of 17 days (46%) forcompound-treated mice.

For survival studies in the xenotransplantation MOLM13 xenograft model,6 to 8-week old female NSG mice were intravenously injected with 0.5×10⁶MOLM13 cells harboring MLL-F9 translocation. At day 4 aftertransplantation, treatment was initiated with Compound C, 75 mg/kg,b.i.d., p.o. or vehicle (20% 2-hydroxypropyl-b-cyclodextrin with 5%cremophore) and was continued for 16 consecutive days in the compoundtreated mice or until terminal leukemia developed in the vehicle-treatedmice. As shown in FIG. 10, Compound C of the present disclosure extendedmedian survival time relative to the vehicle control group.

Similarly, a 120 mg/kg b.i.d. treatment regimen of Compound D wasinitiated on day 6 after MOLM13 transplantation and continued for 16consecutive days in the compound treated mice or until terminal leukemiadeveloped in the vehicle-treated mice. As shown in FIG. 13, Compound Dof the present disclosure extended the median survival time to 24 days,relative to a median survival time of 16 days for mice in the vehiclecontrol group, indicating a survival benefit of 18 days (75%) forcompound-treated mice.

While preferred embodiments of the present disclosure have been shownand described herein, it will be obvious to those skilled in the artthat such embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the disclosure. It should beunderstood that various alternatives to the embodiments of thedisclosure described herein may be employed in practicing the invention.It is intended that the following claims define the scope of theinvention and that methods and structures within the scope of theseclaims and their equivalents be covered thereby.

1. (canceled)
 2. A method of treating a disease or condition in asubject, comprising administering to the subject a therapeuticallyeffective amount of a compound of Formula (II-A):

or a pharmaceutically acceptable salt thereof, wherein: C is selectedfrom C₃₋₁₂ carbocycle and 3- to 12-membered heterocycle; L² is selectedfrom bond, —O—, —S—, —N(R⁵¹)—, —N(R⁵¹)CH₂—, —C(O)—, —C(O)O—, —OC(O)—,—OC(O)O—, —C(O)N(R⁵¹)—, —C(O)N(R⁵¹)C(O)—, —C(O)N(R⁵¹)C(O)N(R⁵¹)—,—N(R⁵¹)C(O)—, —N(R⁵¹)C(O)N(R⁵¹)—, —N(R⁵¹)C(O)O—, —OC(O)N(R⁵¹)—,—C(NR⁵¹)—, —N(R⁵¹)C(NR⁵¹)—, —C(NR⁵¹)N(R⁵¹)—, —N(R⁵¹)C(NR⁵¹)N(R⁵¹)—,—S(O)₂—, —OS(O)—, —S(O)O—, —S(O)—, —OS(O)₂—, —S(O)₂₀—, —N(R⁵¹)S(O)₂—,—S(O)₂N(R⁵¹)—, —N(R⁵¹)S(O)—, —S(O)N(R⁵¹)—, —N(R⁵¹)S(O)₂N(R⁵¹)—,—N(R⁵¹)S(O)N(R⁵¹)—, alkylene, alkenylene, alkynylene, heteroalkylene,heteroalkenylene, and heteroalkynylene, each of which is optionallysubstituted with one or more R⁵⁰; L³ is selected from alkylene,alkenylene, and alkynylene, each of which is substituted with one ormore R⁵⁶ and optionally further substituted with one or more R⁵⁰; R¹ andR³ are each independently selected from hydrogen and R⁵⁰; R² is R⁵⁰;R^(A), R^(B) and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups, or two R^(C)groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring; m, n, and p are each independently aninteger from 0 to 6; R⁵⁰ is independently selected at each occurrencefrom: halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,—S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR″R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR″R⁵⁴, —NR⁵²C(O)^(R52,) _(—NR)⁵²C(₀)_(0R52), —NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂,—C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, and ═N(R⁵²); C₁₋₁₀alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,—S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle; and C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle, wherein each C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle in R⁵⁰ is independently optionally substituted with one ormore substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,—N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,—OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)²,—NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl; R⁵¹ is independently selected at each occurrence from:hydrogen, —C(O)R⁵², —C(O)OR⁵², —C(O)N(R⁵²)₂, and —C(O)NR⁵³R⁵⁴; and C₁₋₆alkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl, each of which is independentlyoptionally substituted at each occurrence with one or more substituentsselected from halogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴,—S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂ carbocycle,. and 3- to12-membered heterocycle; and C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle, wherein each C₃₋₁₂ carbocycle and 3- to 12-memberedheterocycle in R⁵¹ is independently optionally substituted with one ormore substituents selected from halogen, —NO₂, —CN, —OR⁵², —SR⁵²,—N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,—OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)²,—NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl; R⁵² is independently selected at each occurrence from hydrogen;and C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, C₁₋₆ heteroalkyl, C₃₋₁₂carbocycle, and 3- to 12-membered heterocycle, each of which isoptionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃,═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to 6-memberedheterocycle; R⁵³ and R⁵⁴ are taken together with the nitrogen atom towhich they are attached to form a heterocycle, optionally substitutedwith one or more R⁵⁰; R⁵⁶ is independently selected at each occurrencefrom: —NO₂, —OR⁵⁹, —SR⁵², —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,—S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,—NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,—OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)², —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl,C₂₋₁₀ alkynyl, C₃₋₁₂ carbocycle,. and 3- to 12-membered heterocycle,wherein each C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, and C₂₋₁₀ alkynyl in R⁵⁶ isindependently optionally substituted at each occurrence with one or moresubstituents selected from halogen, —NO₂, —CN, —OR⁵⁹, —SR⁵², —N(R⁵²)₂,—NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵²,—C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴,—NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴,—C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²),C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle; wherein each C₃₋₁₂carbocycle and 3- to 12-membered heterocycle in R⁵⁶ is independentlyoptionally substituted with one or more substituents selected fromhalogen, —NO₂, —CN, —OR⁵², —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵²,—S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²,—NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵²,—OC(O)OR⁵², —OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂,—C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₁₋₆ alkyl,C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆ alkynyl; and further wherein R⁵⁶optionally forms a bond to ring C; and R⁵⁹ is independently selected ateach occurrence from C₁₋₂₀ alkyl, C₂₋₂₀ alkenyl, C₂₋₂₀ alkynyl, C₁₋₆heteroalkyl, C₃₋₁₂ carbocycle, and 3- to 12-membered heterocycle, eachof which is optionally substituted by halogen, —CN, —NO₂, —NH₂, —NHCH₃,—NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃, C₃₋₁₂ carbocycle, or 3- to6-membered heterocycle, wherein for a compound or salt of Formula(II-A), when R⁵⁶ is —CH₃, L³ is not further substituted with —OH, —NH₂,or —CN.
 3. The method of claim 2, wherein R^(C) is selected from—C(O)R⁵², —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴,—NR⁵²S(═O)₂R⁵², ═O, C₁₋₃ alkyl, and C₁₋₃ haloalkyl, or two R^(C) groupsattached to different atoms can together form a C₁₋₃ bridge.
 4. Themethod of claim 2 wherein C is 5- to 12-membered saturated heterocycle,wherein the heterocycle comprises at least one nitrogen atom. 5-8.(canceled)
 9. The method of claim 2, wherein C is selected from:

wherein R⁵⁷ is selected from —S(—50 O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵²; and C₁₋₁₀ alkyl substituted with one ormore substituents selected from —S(—50 O)R⁵², —S(═O)₂R⁵²,—S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, and —NR⁵²S(═O)₂R⁵². 10-17. (canceled)18. The method of claim 2, wherein: R² is selected from hydrogen,halogen, —OH, —OR⁵², —NH₂, —N(R⁵²)₂, —CN, C₁₋₃ alkyl, C₁₋₃alkyl-N(R⁵²)₂, C₁₋₃ haloalkyl, C₂₋₃ alkenyl, and C₂₋₃ alkynyl; and R³ isselected from hydrogen, halogen, —OH, —N(R⁵²)₂, —CN, —C(O)OR⁵², C₁₋₃alkyl, and C₁₋₃ haloalkyl. 19-21. (canceled)
 22. The method of claim 2,wherein R¹ is C₁₋₃ haloalkyl. 23-33. (canceled)
 34. The method of claim2 wherein m is
 0. 35. The method of claim 2 wherein n is an integer from1 to
 3. 36-38. (canceled)
 39. The method of claim 2, wherein L² is C₁₋₄alkylene, optionally substituted with one or more R⁵⁰. 40-43. (canceled)44. The method of claim 2, wherein L³ is substituted with ═O, C₁₋₆alkyl, C₁₋₆ haloalkyl, C₁₋₃ alkyl(cyclopropyl), C₁₋₃ alkyl(NR⁵²C(O)R⁵²)or —O(C₁₋₆ alkyl). 45-47. (canceled)
 48. The method of claim 2, whereinL³ is selected from


49. The method of claim 48, wherein R⁵⁶ is methyl.
 50. (canceled) 51.(canceled)
 52. The method of claim 2, wherein: L² is selected from —O—,—S—, —NH—, and —CH₂—; L³ is selected from C₁₋₆ alkylene, C₂₋₆alkenylene, and C₂₋₆ alkynylene, each of which is substituted with oneor more R⁵⁶ and optionally further substituted with one or more R⁵⁰;R^(A), R^(B), and R^(C) are each independently selected at eachoccurrence from R⁵⁰, or two R^(A) groups, two R^(B) groups,, or twoR^(C) groups attached to the same atom or different atoms can togetheroptionally form a bridge or ring; m is an integer from 0 to 3; n is aninteger from 1 to 3; p is an integer from 0 to 6; R⁵⁶ is independentlyselected at each occurrence from: —OR⁵⁹, —O—, C₁₋₁₀ alkyl, C₂₋₁₀alkenyl, and C₂₋₁₀ alkynyl, wherein each C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, andC₂₋₁₀ alkynyl in R⁵⁶ is independently optionally substituted at eachoccurrence with one or more substituents selected from halogen, —NO₂,—CN, —OR⁵⁹, —SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵²,—S(═O)₂N(R⁵²)₂, —S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂,—NR⁵²S(═O)₂NR⁵³R⁵⁴, —C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵²,—OC(O)N(R⁵²)₂, —OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵²,—NR⁵²C(O)N(R⁵²)₂, —NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴,—P(O)(OR⁵²)₂, —P(O)(R⁵²)₂, ═O, ═S, ═N(R⁵²), C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle; wherein each C₃₋₁₂ carbocycle and 3- to12-membered heterocycle in R⁵⁶ is independently optionally substitutedwith one or more substituents selected from halogen, —NO₂, —CN, —OR⁵²,—SR⁵², —N(R⁵²)₂, —NR⁵³R⁵⁴, —S(═O)R⁵², —S(═O)₂R⁵², —S(═O)₂N(R⁵²)₂,—S(═O)₂NR⁵³R⁵⁴, —NR⁵²S(═O)₂R⁵², —NR⁵²S(═O)₂N(R⁵²)₂, —NR⁵²S(═O)₂NR⁵³R⁵⁴,—C(O)R⁵², —C(O)OR⁵², —OC(O)R⁵², —OC(O)OR⁵², —OC(O)N(R⁵²)₂,—OC(O)NR⁵³R⁵⁴, —NR⁵²C(O)R⁵², —NR⁵²C(O)OR⁵², —NR⁵²C(O)N(R⁵²)₂,—NR⁵²C(O)NR⁵³R⁵⁴, —C(O)N(R⁵²)₂, —C(O)NR⁵³R⁵⁴, —P(O)(OR⁵²)₂, —P(O)(R⁵²)₂,═O, ═S, ═N(R⁵²), C₁₋₆ alkyl, C₁₋₆ haloalkyl, C₂₋₆ alkenyl, and C₂₋₆alkynyl; and further wherein R⁵⁶ optionally forms a bond to ring C; andR⁵⁹ is independently selected at each occurrence from C₁₋₂₀ alkyl, C₂₋₂₀alkenyl, C₂₋₂₀ alkynyl, C₁₋₆ heteroalkyl, C₃₋₁₂ carbocycle, and 3- to12-membered heterocycle, each of which is optionally substituted byhalogen, —CN, —NO₂, —NH₂, —NHCH₃, —NHCH₂CH₃, ═O, —OH, —OCH₃, —OCH₂CH₃,C₃₋₁₂ carbocycle, or 3- to 6-membered heterocycle.
 53. (canceled) 54.(canceled)
 55. The method of claim 52, wherein p is 1 and R^(C) is—S(—50 O)₂R⁵⁸, —S(═O)₂N(R⁵²)₂, or —S(—50 O)₂NR⁵³R⁵⁴. 56-59. (canceled)60. The method of claim 52, wherein the stereoisomer is provided in atleast 90% enantiomeric excess. 61-73. (canceled)
 74. The method of claim2, wherein the disease or condition is associated with MLL fusionproteins. 75-77. (canceled)
 78. The method of claim 2, wherein thedisease or condition is mediated by chromosomal rearrangement onchromosome 11q23.
 79. The method of claim 2, wherein the disease orcondition is mediated by an interaction between menin and anotherprotein.
 80. (canceled)
 81. (canceled)
 82. The method of claim 2.wherein the compound has the structure of Formula (II-C):


83. The method of claim 2, wherein the compound has the structure ofFormula (II-F) or Formula (II-H):


84. The method of claim 2, wherein the compound is selected from thegroup consisting of:

or a pharmaceutically acceptable salt thereof
 85. The method of claim 2,wherein the compound is:

or a pharmaceutically acceptable salt thereof.